Fluticasone and salmeterol: uses, appearance and warnings

Fluticasone propionate and salmeterol inhalation powder is a combination product containing a corticosteroid and a long-acting beta2-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.

Inhalation powder: Inhaler containing a foil blister strip of powder formulation for oral inhalation. The strip contains a combination of fluticasone propionate 100, 250, or 500 mcg and salmeterol 50 mcg per blister. Inhalation powder: Inhaler containing a combination of fluticasone propionate (100, 250, or 500 mcg) and salmeterol (50 mcg) as a powder formulation for oral inhalation. ( 3 )

Fluticasone propionate and salmeterol inhalation powder, USP 100 mcg/50 mcg is supplied as a disposable blue-white plastic inhaler containing a foil blister strip with 60 blisters. The inhaler is packaged in a plastic-coated, moisture-protective foil pouch (NDC 69097-662-03). Fluticasone propionate and salmeterol inhalation powder, USP 250 mcg/50 mcg is supplied as a disposable blue-white plastic inhaler containing a foil blister strip with 60 blisters. The inhaler is packaged in a plastic-coated, moisture-protective foil pouch (NDC 69097-661-03). Fluticasone propionate and salmeterol inhalation powder, USP 500 mcg/50 mcg is supplied as a disposable blue-white plastic inhaler containing a foil blister strip with 60 blisters. The inhaler is packaged in a plastic-coated, moisture-protective foil pouch (NDC 69097-663-03). Store at room temperature between 68°F and 77°F (20°C and 25°C); excursions permitted from 59°F to 86°F (15°C to 30°C) [See USP Controlled Room Temperature]. Store in a dry place away from direct heat or sunlight. Keep out of reach of children. Fluticasone propionate and salmeterol inhalation powder, USP should be stored inside the unopened moisture-protective foil pouch and only removed from the pouch immediately before initial use. Discard fluticasone propionate and salmeterol inhalation powder 1 month after opening the foil pouch or when the counter reads “0” (after all blisters have been used), whichever comes first. The inhaler is not reusable. Do not attempt to take the inhaler apart.

The use of fluticasone propionate and salmeterol inhalation powder is contraindicated in the following conditions: Primary treatment of status asthmaticus or other acute episodes of asthma or COPD where intensive measures are required [see Warnings and Precautions (5.2)] . Severe hypersensitivity to milk proteins or demonstrated hypersensitivity to fluticasone propionate, salmeterol, or any of the excipients [see Warnings and Precautions (5.11), Adverse Reactions (6.3), Description (11)] . Primary treatment of status asthmaticus or acute episodes of asthma or COPD requiring intensive measures. ( 4 ) Severe hypersensitivity to milk proteins or demonstrated hypersensitivity to fluticasone propionate, salmeterol, or any of the excipients. ( 4 )

LABA monotherapy increases the risk of serious asthma-related events. ( 5.1 ) Do not initiate in acutely deteriorating asthma or COPD. Do not use to treat acute symptoms. ( 5.2 ) Do not use in combination with an additional medicine containing a LABA because of risk of overdose. ( 5.3 ) 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 ) Increased risk of pneumonia in patients with COPD. Monitor patients for signs and symptoms of pneumonia. ( 5.5 ) Potential worsening of infections (e.g., existing tuberculosis; fungal, bacterial, viral, or parasitic infections; 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. ( 5.6 ) Risk of impaired adrenal function when transferring from systemic corticosteroids. Taper patients slowly from systemic corticosteroids if transferring to fluticasone propionate and salmeterol inhalation powder. ( 5.7 ) 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 and salmeterol inhalation powder slowly. ( 5.8 ) If paradoxical bronchospasm occurs, discontinue fluticasone propionate and salmeterol inhalation powder and institute alternative therapy. ( 5.10 ) Use with caution in patients with cardiovascular or central nervous system disorders because of beta-adrenergic stimulation. ( 5.12 ) Assess for decrease in bone mineral density initially and periodically thereafter. ( 5.13 ) Monitor growth of pediatric patients. ( 5.14 ) Glaucoma and cataracts may occur with long-term use of inhaled corticosteroids. Consider referral to an ophthalmologist in patients who develop ocular symptoms or use fluticasone propionate and salmeterol inhalation powder long term. ( 5.15 ) Be alert to eosinophilic conditions, hypokalemia, and hyperglycemia. ( 5.16 , 5.18 ) Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis. ( 5.17 ) 5.1 Serious Asthma-Related Events – Hospitalizations, Intubations, Death Use of LABA as monotherapy (without 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 (4) large, 26-week, randomized, double-blind, 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 fluticasone propionate and salmeterol inhalation powder with fluticasone propionate inhalation powder [see Clinical Studies (14.1)] , 1 trial compared mometasone furoate/formoterol with mometasone furoate, and 1 trial compared budesonide/formoterol with budesonide. The fourth trial included pediatric subjects aged 4 to 11 years and compared fluticasone propionate and salmeterol inhalation powder with fluticasone propionate inhalation powder [see Clinical Studies (14.1)] . 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 Asthma-related death Asthma-related intubation (endotracheal) Asthma-related hospitalization (≥24-hour stay) 116 2 1 115 105 0 2 105 1.10 (0.85, 1.44) 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 event 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. …

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 di …

Fluticasone propionate and salmeterol inhalation powder has been used concomitantly with other drugs, including short-acting beta 2 -agonists, methylxanthines, and intranasal corticosteroids, commonly used in patients with asthma or COPD without adverse drug reactions [see Clinical Pharmacology (12.2)] . No formal drug interaction trials have been performed with fluticasone propionate and salmeterol inhalation powder. Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir, ketoconazole): Use not recommended. 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. …