Fluticasone Propionate and Salmeterol DISKUS (Page 8 of 13)

11 DESCRIPTION

Fluticasone Propionate/Salmeterol DISKUS inhalation powder 100/50 mcg, Fluticasone Propionate/Salmeterol DISKUS inhalation powder 250/50 mcg, and Fluticasone Propionate/Salmeterol DISKUS inhalation powder 500/50 mcg are combinations of fluticasone propionate and salmeterol xinafoate.

One active component of Fluticasone Propionate/Salmeterol DISKUS is fluticasone propionate, a corticosteroid having the chemical name S- (fluoromethyl) 6α,9-difluoro-11β,17-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate, 17-propionate and the following chemical structure:

Fluticasone propionate chemical structure

Fluticasone propionate is a white powder with a molecular weight of 500.6, and the empirical formula is C25 H31 F3 O5 S. It is practically insoluble in water, freely soluble in dimethyl sulfoxide and dimethylformamide, and slightly soluble in methanol and 95% ethanol.

The other active component of Fluticasone Propionate/Salmeterol DISKUS is salmeterol xinafoate, a beta2 -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-α1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol, 1-hydroxy-2-naphthalenecarboxylate and the following chemical structure:

Salmeterol xinafoate chemical structure
(click image for full-size original)

Salmeterol xinafoate is a white powder with a molecular weight of 603.8, and the empirical formula is C25 H37 NO4 •C11 H8 O3 . It is freely soluble in methanol; slightly soluble in ethanol, chloroform, and isopropanol; and sparingly soluble in water.

Fluticasone Propionate/Salmeterol DISKUS is a purple plastic inhaler containing a foil blister strip. Each blister on the strip contains a white powder mix of micronized fluticasone propionate (100, 250, or 500 mcg) and micronized salmeterol xinafoate salt (72.5 mcg, equivalent to 50 mcg of salmeterol base) in 12.5 mg of formulation containing lactose monohydrate (which contains milk proteins). After the inhaler is activated, the powder is dispersed into the airstream created by the patient inhaling through the mouthpiece.

Under standardized in vitro test conditions, Fluticasone Propionate/Salmeterol DISKUS delivers 93, 233, and 465 mcg of fluticasone propionate and 45 mcg of salmeterol base per blister from Fluticasone Propionate/Salmeterol DISKUS inhalation powder 100/50 mcg, Fluticasone Propionate/Salmeterol DISKUS inhalation powder 250/50 mcg, and Fluticasone Propionate/Salmeterol DISKUS inhalation powder 500/50 mcg, respectively, when tested at a flow rate of 60 L/min for 2 seconds.

In adult subjects with obstructive lung disease and severely compromised lung function (mean FEV1 20% to 30% of predicted), mean peak inspiratory flow (PIF) through the DISKUS inhaler was 82.4 L/min (range: 46.1 to 115.3 L/min).

Inhalation profiles for adolescent (N = 13, aged 12 to 17 years) and adult (N = 17, aged 18 to 50 years) subjects with asthma inhaling maximally through the DISKUS inhaler show mean PIF of 122.2 L/min (range: 81.6 to 152.1 L/min). Inhalation profiles for pediatric subjects with asthma inhaling maximally through the DISKUS inhaler show a mean PIF of 75.5 L/min (range: 49.0 to 104.8 L/min) for the 4-year-old subject set (N = 20) and 107.3 L/min (range: 82.8 to 125.6 L/min) for the 8-year-old subject set (N = 20).

The actual amount of drug delivered to the lung will depend on patient factors, such as inspiratory flow profile.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Fluticasone Propionate/Salmeterol DISKUS

Fluticasone Propionate/Salmeterol DISKUS contains both fluticasone propionate and salmeterol. The mechanisms of action described below for the individual components apply to Fluticasone Propionate/Salmeterol DISKUS. 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 man 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, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in inflammation. These anti-inflammatory actions of corticosteroids contribute to their efficacy in asthma.

Inflammation is also a component in the pathogenesis of COPD. In contrast to asthma, however, the predominant inflammatory cells in COPD include neutrophils, CD8+ T-lymphocytes, and macrophages. The effects of corticosteroids in the treatment of COPD are not well defined and ICS and fluticasone propionate when used apart from Fluticasone Propionate/Salmeterol DISKUS are not indicated for the treatment of COPD.

Salmeterol Xinafoate

Salmeterol is a selective LABA. In vitro studies show salmeterol to be at least 50 times more selective for beta2 -adrenoceptors than albuterol. Although beta2 -adrenoceptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1 -adrenoceptors are the predominant receptors in the heart, there are also beta2 -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 beta2 -agonists may have cardiac effects.

The pharmacologic effects of beta2 -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 D2 , 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 hyper-responsiveness.

12.2 Pharmacodynamics

Fluticasone Propionate/Salmeterol DISKUS

Healthy Subjects: Cardiovascular Effects: Since systemic pharmacodynamic effects of salmeterol are not normally seen at the therapeutic dose, higher doses were used to produce measurable effects. Four (4) trials were conducted with healthy adult subjects: (1) a single-dose crossover trial using 2 inhalations of fluticasone propionate/salmeterol DISKUS 500/50 mcg, fluticasone propionate inhalation powder 500 mcg and salmeterol inhalation powder 50 mcg given concurrently, or fluticasone propionate inhalation powder 500 mcg given alone, (2) a cumulative-dose trial using 50 to 400 mcg of salmeterol inhalation powder given alone or as fluticasone propionate/salmeterol DISKUS 500/50 mcg, (3) a repeat-dose trial for 11 days using 2 inhalations twice daily of fluticasone propionate/salmeterol DISKUS 250/50 mcg, fluticasone propionate inhalation powder 250 mcg, or salmeterol inhalation powder 50 mcg, and (4) a single‑dose trial using 5 inhalations of fluticasone propionate/salmeterol DISKUS 100/50 mcg, fluticasone propionate inhalation powder 100 mcg alone, or placebo. In these trials no significant differences were observed in the pharmacodynamic effects of salmeterol (pulse rate, blood pressure, QTc interval, potassium, and glucose) whether the salmeterol was given as fluticasone propionate/salmeterol DISKUS, concurrently with fluticasone propionate from separate inhalers, or as salmeterol alone. The systemic pharmacodynamic effects of salmeterol were not altered by the presence of fluticasone propionate in fluticasone propionate/salmeterol DISKUS. The potential effect of salmeterol on the effects of fluticasone propionate on the HPA axis was also evaluated in these trials.

Hypothalamic-Pituitary-Adrenal Axis Effects: No significant differences across treatments were observed in 24-hour urinary cortisol excretion and, where measured, 24-hour plasma cortisol AUC. The systemic pharmacodynamic effects of fluticasone propionate were not altered by the presence of salmeterol in fluticasone propionate/salmeterol DISKUS in healthy subjects.

Subjects with Asthma: Adult and Adolescent Subjects: Cardiovascular Effects: In clinical trials with fluticasone propionate/salmeterol DISKUS in adult and adolescent subjects aged 12 years and older with asthma, no significant differences were observed in the systemic pharmacodynamic effects of salmeterol (pulse rate, blood pressure, QTc interval, potassium, and glucose) whether the salmeterol was given alone or as fluticasone propionate/salmeterol DISKUS. In 72 adult and adolescent subjects with asthma given either fluticasone propionate/salmeterol DISKUS 100/50 mcg or fluticasone propionate/salmeterol DISKUS 250/50 mcg, continuous 24-hour electrocardiographic monitoring was performed after the first dose and after 12 weeks of therapy, and no clinically significant dysrhythmias were noted.

Hypothalamic-Pituitary-Adrenal Axis Effects: In a 28-week trial in adult and adolescent subjects with asthma, fluticasone propionate/salmeterol DISKUS 500/50 mcg twice daily was compared with the concurrent use of salmeterol inhalation powder 50 mcg plus fluticasone propionate inhalation powder 500 mcg from separate inhalers or fluticasone propionate inhalation powder 500 mcg alone. No significant differences across treatments were observed in serum cortisol AUC after 12 weeks of dosing or in 24-hour urinary cortisol excretion after 12 and 28 weeks.

In a 12-week trial in adult and adolescent subjects with asthma, fluticasone propionate/salmeterol DISKUS 250/50 mcg twice daily was compared with fluticasone propionate inhalation powder 250 mcg alone, salmeterol inhalation powder 50 mcg alone, and placebo. For most subjects, the ability to increase cortisol production in response to stress, as assessed by 30-minute cosyntropin stimulation, remained intact with fluticasone propionate/salmeterol DISKUS. One subject (3%) who received fluticasone propionate/salmeterol DISKUS 250/50 mcg had an abnormal response (peak serum cortisol <18 mcg/dL) after dosing, compared with 2 subjects (6%) who received placebo, 2 subjects (6%) who received fluticasone propionate 250 mcg, and no subjects who received salmeterol.

In a repeat-dose, 3-way crossover trial, 1 inhalation twice daily of fluticasone propionate/salmeterol DISKUS 100/50 mcg, FLOVENT DISKUS 100 mcg (fluticasone propionate inhalation powder 100 mcg), or placebo was administered to 20 adult and adolescent subjects with asthma. After 28 days of treatment, geometric mean serum cortisol AUC over 12 hours showed no significant difference between fluticasone propionate/salmeterol DISKUS and FLOVENT DISKUS or between either active treatment and placebo.

Pediatric Subjects: Hypothalamic-Pituitary-Adrenal Axis Effects: In a 12-week trial in subjects with asthma aged 4 to 11 years who were receiving ICS at trial entry, fluticasone propionate/salmeterol DISKUS 100/50 mcg twice daily was compared with fluticasone propionate inhalation powder 100 mcg administered twice daily via the DISKUS. The values for 24-hour urinary cortisol excretion at trial entry and after 12 weeks of treatment were similar within each treatment group. After 12 weeks, 24-hour urinary cortisol excretion was also similar between the 2 groups.

Subjects with Chronic Obstructive Pulmonary Disease: Cardiovascular Effects: In clinical trials with fluticasone propionate/salmeterol DISKUS in subjects with COPD, no significant differences were seen in pulse rate, blood pressure, potassium, and glucose between fluticasone propionate/salmeterol DISKUS, the individual components of fluticasone propionate/salmeterol DISKUS, and placebo. In a trial of fluticasone propionate/salmeterol DISKUS 250/50 mcg, 8 subjects (2 [1.1%] in the group given fluticasone propionate/salmeterol DISKUS 250/50 mcg, 1 [0.5%] in the fluticasone propionate 250-mcg group, 3 [1.7%] in the salmeterol group, and 2 [1.1%] in the placebo group) had QTc intervals >470 msec at least 1 time during the treatment period. Five (5) of these 8 subjects had a prolonged QTc interval at baseline.

In a 24-week trial, 130 subjects with COPD received continuous 24-hour electrocardiographic monitoring prior to the first dose and after 4 weeks of twice-daily treatment with either fluticasone propionate/salmeterol DISKUS 500/50 mcg, fluticasone propionate inhalation powder 500 mcg, salmeterol inhalation powder 50 mcg, or placebo. No significant differences in ventricular or supraventricular arrhythmias and heart rate were observed among the groups treated with fluticasone propionate/salmeterol DISKUS 500/50 mcg, the individual components, or placebo. One (1) subject in the fluticasone propionate group experienced atrial flutter/atrial fibrillation, and 1 subject in the group given fluticasone propionate/salmeterol DISKUS 500/50 mcg experienced heart block. There were 3 cases of nonsustained ventricular tachycardia (1 each in the placebo, salmeterol, and fluticasone propionate 500-mcg treatment groups).

In 24-week clinical trials in subjects with COPD, the incidence of clinically significant ECG abnormalities (myocardial ischemia, ventricular hypertrophy, clinically significant conduction abnormalities, clinically significant arrhythmias) was lower for subjects who received salmeterol (1%, 9 of 688 subjects who received either salmeterol 50 mcg or fluticasone propionate/salmeterol DISKUS) compared with placebo (3%, 10 of 370 subjects).

No significant differences with salmeterol 50 mcg alone or in combination with fluticasone propionate as fluticasone propionate/salmeterol DISKUS 500/50 mcg were observed on pulse rate and systolic and diastolic blood pressure in a subset of subjects with COPD who underwent 12-hour serial vital sign measurements after the first dose (n = 183) and after 12 weeks of therapy (n = 149). Median changes from baseline in pulse rate and systolic and diastolic blood pressure were similar to those seen with placebo.

Hypothalamic-Pituitary-Adrenal Axis Effects: Short-cosyntropin stimulation testing was performed both at Day 1 and Endpoint in 101 subjects with COPD receiving twice-daily fluticasone propionate/salmeterol DISKUS 250/50 mcg, fluticasone propionate inhalation powder 250 mcg, salmeterol inhalation powder 50 mcg, or placebo. For most subjects, the ability to increase cortisol production in response to stress, as assessed by short cosyntropin stimulation, remained intact with fluticasone propionate/salmeterol DISKUS 250/50 mcg. One (1) subject (3%) who received fluticasone propionate/salmeterol DISKUS 250/50 mcg had an abnormal stimulated cortisol response (peak cortisol <14.5 mcg/dL assessed by high-performance liquid chromatography) after dosing, compared with 2 subjects (9%) who received fluticasone propionate 250 mcg, 2 subjects (7%) who received salmeterol 50 mcg, and 1 subject (4%) who received placebo following 24 weeks of treatment or early discontinuation from trial.

After 36 weeks of dosing, serum cortisol concentrations in a subset of subjects with COPD (n = 83) were 22% lower in subjects receiving fluticasone propionate/salmeterol DISKUS 500/50 mcg and 21% lower in subjects receiving fluticasone propionate 500 mcg than in subjects receiving placebo.

Other Fluticasone Propionate Products

Subjects with Asthma: Hypothalamic-Pituitary-Adrenal Axis Effects: In clinical trials with fluticasone propionate inhalation powder using dosages up to and including 250 mcg twice daily, occasional abnormal short cosyntropin tests (peak serum cortisol <18 mcg/dL assessed by radioimmunoassay) were noted both in subjects receiving fluticasone propionate and in subjects receiving placebo. The incidence of abnormal tests at 500 mcg twice daily was greater than placebo. In a 2-year trial carried out with the DISKHALER inhalation device in 64 subjects with mild, persistent asthma (mean FEV1 91% of predicted) randomized to fluticasone propionate 500 mcg twice daily or placebo, no subject receiving fluticasone propionate had an abnormal response to 6-hour cosyntropin infusion (peak serum cortisol <18 mcg/dL). With a peak cortisol threshold of <35 mcg/dL, 1 subject receiving fluticasone propionate (4%) had an abnormal response at 1 year; repeat testing at 18 months and 2 years was normal. Another subject receiving fluticasone propionate (5%) had an abnormal response at 2 years. No subject on placebo had an abnormal response at 1 or 2 years.

Subjects with Chronic Obstructive Pulmonary Disease: Hypothalamic-Pituitary-Adrenal Axis Effects: After 4 weeks of dosing, the steady-state fluticasone propionate pharmacokinetics and serum cortisol levels were described in a subset of subjects with COPD (n = 86) randomized to twice-daily fluticasone propionate inhalation powder via the DISKUS 500 mcg, fluticasone propionate inhalation powder 250 mcg, or placebo. Serial serum cortisol concentrations were measured across a 12-hour dosing interval. Serum cortisol concentrations following 250- and 500-mcg twice-daily dosing were 10% and 21% lower than placebo, respectively, indicating a dose-dependent increase in systemic exposure to fluticasone propionate.

Other Salmeterol Xinafoate Products

Subjects with Asthma: Cardiovascular Effects: Inhaled salmeterol, like other beta-adrenergic agonist drugs, can produce dose-related cardiovascular effects and effects on blood glucose and/or serum potassium [see Warnings and Precautions (5.12, 5.18)]. The cardiovascular effects (heart rate, blood pressure) associated with salmeterol inhalation aerosol occur with similar frequency, and are of similar type and severity, as those noted following albuterol administration.

The effects of rising inhaled doses of salmeterol and standard inhaled doses of albuterol were studied in volunteers and in subjects with asthma. Salmeterol doses up to 84 mcg administered as inhalation aerosol resulted in heart rate increases of 3 to 16 beats/min, about the same as albuterol dosed at 180 mcg by inhalation aerosol (4 to 10 beats/min). Adult and adolescent subjects receiving 50-mcg doses of salmeterol inhalation powder (N = 60) underwent continuous electrocardiographic monitoring during two 12-hour periods after the first dose and after 1 month of therapy, and no clinically significant dysrhythmias were noted.

Concomitant Use of Fluticasone Propionate/Salmeterol DISKUS with Other Respiratory Medicines

Short-acting Beta2 -agonists: In clinical trials in subjects with asthma, the mean daily need for albuterol by 166 adult and adolescent subjects aged 12 years and older using fluticasone propionate/salmeterol DISKUS was approximately 1.3 inhalations/day and ranged from 0 to 9 inhalations/day. Five percent (5%) of subjects using fluticasone propionate/salmeterol DISKUS in these trials averaged 6 or more inhalations per day over the course of the 12-week trials. No increase in frequency of cardiovascular adverse events was observed among subjects who averaged 6 or more inhalations per day.

In a clinical trial in subjects with COPD, the mean daily need for albuterol for subjects using fluticasone propionate/salmeterol DISKUS 250/50 mcg was 4.1 inhalations/day. Twenty-six percent (26%) of subjects using fluticasone propionate/salmeterol DISKUS 250/50 mcg averaged 6 or more inhalations of albuterol per day over the course of the 24-week trial. No increase in frequency of cardiovascular adverse reactions was observed among subjects who averaged 6 or more inhalations per day.

Methylxanthines: The concurrent use of intravenously or orally administered methylxanthines (e.g., aminophylline, theophylline) by adult and adolescent subjects aged 12 years and older receiving fluticasone propionate/salmeterol DISKUS has not been completely evaluated. In clinical trials in subjects with asthma, 39 subjects receiving fluticasone propionate/salmeterol DISKUS 100/50 mcg, fluticasone propionate/salmeterol DISKUS 250/50 mcg, or fluticasone propionate/salmeterol DISKUS 500/50 mcg twice daily concurrently with a theophylline product had adverse event rates similar to those in 304 subjects receiving fluticasone propionate/salmeterol DISKUS without theophylline. Similar results were observed in subjects receiving salmeterol 50 mcg plus fluticasone propionate 500 mcg twice daily concurrently with a theophylline product (n = 39) or without theophylline (n = 132).

In a clinical trial in subjects with COPD, 17 subjects receiving fluticasone propionate/salmeterol DISKUS 250/50 mcg twice daily concurrently with a theophylline product had adverse event rates similar to those in 161 subjects receiving fluticasone propionate/salmeterol DISKUS without theophylline. Based on the available data, the concomitant administration of methylxanthines with fluticasone propionate/salmeterol DISKUS did not alter the observed adverse event profile.

Fluticasone Propionate Nasal Spray: In adult and adolescent subjects aged 12 years and older receiving fluticasone propionate/salmeterol DISKUS in clinical trials, no difference in the profile of adverse events or HPA axis effects was noted between subjects who were receiving FLONASE (fluticasone propionate) Nasal Spray, 50 mcg concurrently (n = 46) and those who were not (n = 130).

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