Fluticasone Propionate And Salmeterol

Introduction Overview

Generic Name

fluticasone propionate and salmeterol

Brand Name

Wixela Inhub

Dosage Form

inhalation powder

Drug Class

Bronchodilator combinations

Pharmacokinetics

Absorption:
Fluticasone propionate acts locally in the lung with negligible oral systemic bioavailability (<1%) due to incomplete absorption and extensive first-pass metabolism. After inhalation of Wixela Inhub, peak plasma levels of fluticasone propionate are reached within 1 to 2 hours. Systemic exposure was similar between fluticasone propionate and salmeterol inhalation powder and ADVAIR HFA for comparable doses, with absolute bioavailability around 5.3-5.5%. Salmeterol xinafoate dissociates rapidly in solution, with peak plasma concentrations observed about 5 minutes post-inhalation. In asthma patients, salmeterol concentrations are low or undetectable at therapeutic doses, with mean peak plasma concentration around 167 pg/mL occurring at approximately 20 minutes post-dose.

Distribution:
Fluticasone propionate demonstrates a high volume of distribution (~4.2 L/kg) and is extensively bound to plasma proteins (~99%) with weak reversible binding to erythrocytes and no significant transcortin binding. Salmeterol is highly protein-bound (~96%), at concentrations much higher than therapeutic levels, indicating a strong binding affinity but low free fraction in plasma.

Metabolism:
Fluticasone propionate is extensively metabolized by CYP3A4 to an inactive 17β-carboxylic acid metabolite, with negligible renal clearance (<0.02%). Salmeterol undergoes extensive hepatic metabolism primarily via CYP3A4 to α-hydroxysalmeterol, with elimination predominantly via feces. In vitro, ketoconazole, a CYP3A4 inhibitor, markedly reduces salmeterol metabolism, increasing systemic exposure.

Elimination:
Fluticasone propionate exhibits polyexponential kinetics with a terminal elimination half-life of approximately 7.8 hours, with majority of drug excreted in feces. Salmeterol has a terminal half-life of about 5.5 hours; approximately 25% is excreted in urine and 60% in feces following oral administration. The xinafoate moiety has no pharmacologic activity and a long half-life (~11 days).

Specific Populations:
Pharmacokinetic analyses indicate no clinically relevant differences in clearance or volume of distribution of either component with age, gender, race, body weight, BMI, or baseline lung function. Pediatric patients (4 to 11 years) demonstrate higher systemic exposure to both drugs compared to adults, yet no increase in adverse systemic effects was observed. Hepatic impairment may lead to increased plasma concentrations due to predominant hepatic metabolism, thus requiring close monitoring. No formal studies have been performed in renal impairment.

Dosage Forms

Available Dosage Forms:
Wixela Inhub is supplied as a dry powder inhaler with two foil-sealed discs containing a total of 60 pre-metered doses. Each dose consists of a combination of fluticasone propionate and salmeterol xinafoate powder formulated for oral inhalation. The product is available in three strengths:
- Wixela Inhub 100/50 mcg: 100 mcg fluticasone propionate and 50 mcg salmeterol
- Wixela Inhub 250/50 mcg: 250 mcg fluticasone propionate and 50 mcg salmeterol
- Wixela Inhub 500/50 mcg: 500 mcg fluticasone propionate and 50 mcg salmeterol

Dosages for Adults and Adolescents:
- Asthma (≥12 years): One inhalation twice daily of Wixela Inhub 100/50 mcg, 250/50 mcg, or 500/50 mcg based on severity. The starting dose should be selected according to prior asthma therapy and symptom control, with a maximum of 500/50 mcg twice daily.

- Asthma (4-11 years): One inhalation twice daily of the 100/50 mcg strength.

- COPD (≥18 years): Maintenance treatment with one inhalation twice daily of Wixela Inhub 250/50 mcg.

Specific Patient Populations:
- Pediatric patients aged 4 to 11 years are supported for asthma treatment using the 100/50 mcg dose based on extrapolated efficacy and safety data.
- Geriatric patients do not require dosage adjustment; however, caution is advised with concomitant cardiovascular disease.
- Patients with hepatic impairment should be closely monitored due to potential drug accumulation.

Clinical Guidelines:
Patients should follow the prescribed dose exactly, do not exceed one inhalation twice daily. Rinse the mouth after inhalation. Not to be used for acute bronchospasm or exacerbations. Use of additional LABA-containing medications concurrently is contraindicated to prevent overdose.

Mechanism Of Action

Wixela Inhub is a fixed-dose combination of fluticasone propionate and salmeterol, which provides complementary pharmacologic effects through two distinct mechanisms.

Fluticasone propionate is a potent synthetic trifluorinated corticosteroid exhibiting high affinity for human glucocorticoid receptors, approximately 18-fold greater than dexamethasone. It exerts anti-inflammatory effects by modulating multiple cell types such as mast cells, eosinophils, neutrophils, macrophages, and lymphocytes, and inhibiting the release and action of inflammatory mediators including histamine, eicosanoids, leukotrienes, and cytokines. This broad suppression of airway inflammation reduces airway hyperresponsiveness, edema, and mucus production, which are key contributors to asthma pathophysiology and components of chronic obstructive pulmonary disease (COPD) inflammatory milieu.

Salmeterol xinafoate is a selective, long-acting beta2-adrenergic receptor agonist (LABA) with at least 50-fold selectivity over beta1-receptors. Upon binding to beta2-adrenergic receptors located on bronchial smooth muscle, salmeterol activates adenyl cyclase, increasing intracellular cyclic AMP levels, leading to relaxation of bronchial smooth muscle and bronchodilation. Additionally, salmeterol inhibits mast cell mediator release (histamine, leukotrienes, prostaglandin D2), reducing immediate hypersensitivity and airway inflammation. The lipophilic side chain anchors salmeterol near the receptor, conferring prolonged duration of action, sustaining bronchodilation up to 12 hours.

The combination therapy achieves superior bronchodilation and inflammation control compared to monotherapy with either agent, translating into improved pulmonary function, symptom control, and reduced exacerbation rates in asthma and COPD. Clinical studies demonstrate rapid onset of bronchodilation within 30 minutes post-dose and sustained efficacy.

Comparatively, this pharmacodynamic synergy is consistent with other ICS/LABA combinations but Wixela Inhub utilizes fluticasone propionate, which may have a higher glucocorticoid receptor affinity and favorable anti-inflammatory potency, combined with salmeterol that offers long-lasting bronchodilation with a well-characterized safety profile.

Research supports that the corticosteroid component mitigates the increased risk of asthma-related adverse events observed with LABA monotherapy by controlling airway inflammation, underscoring the clinical rationale for fixed-dose combination use to optimize efficacy and safety.

Pharmacological Actions

Inhaled corticosteroid (fluticasone propionate) with potent anti-inflammatory effects reducing airway hyperresponsiveness and edema.
Long-acting beta2-adrenergic agonist (salmeterol) providing sustained bronchodilation by relaxing bronchial smooth muscle.
Reduction of inflammatory mediator release (histamine, leukotrienes, prostaglandins) from mast cells.
Improvement of pulmonary function (increased FEV1, PEF) in asthma and COPD.
Decrease in frequency and severity of asthma and COPD exacerbations with maintenance therapy.
Suppression of eosinophilic inflammation contributing to asthma control.
Selective beta2-adrenergic receptor activity with minimal beta1 cardiac effects, though cardiovascular monitoring advised.
Minimal systemic corticosteroid absorption at recommended doses, reducing systemic adverse effects.
Inhibition of airway remodeling and mucus hypersecretion through long-term corticosteroid action.
Prolonged duration of bronchodilation (up to 12 hours) allowing twice-daily dosing.
Combined action resulting in improved symptom control, quality of life, and exercise tolerance.
Synergistic effect enhancing efficacy compared to either component alone.
Inhibition of airway mast cell degranulation, attenuating immediate hypersensitivity responses.
Decreased airway eosinophils and lymphocytes, critical in asthma pathogenesis.
Reduction in inflammatory cytokine production and expression of adhesion molecules.

Therapeutic Or Clinical Uses

Maintenance treatment of asthma in patients aged 4 years and older requiring both inhaled corticosteroid and long-acting beta2-agonist therapy.
Control of persistent asthma symptoms and prevention of wheezing, breathlessness, and asthma exacerbations.
Maintenance treatment of airflow obstruction in adults with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.
Reduction of COPD exacerbations in patients with a history of exacerbations.
Improvement of pulmonary function metrics such as forced expiratory volume in one second (FEV1) and peak expiratory flow (PEF).
Alternative for patients inadequately controlled on inhaled corticosteroids alone or LABA alone in asthma management.
Adjunct therapy in patients with moderate to severe asthma requiring combination therapy for adequate control.
Use in adults to improve symptoms and reduce exacerbations associated with obstructive lung disease including COPD.
Used for long-term control and prevention rather than relief of acute bronchospasm or exacerbations.
Approved for pediatric asthma maintenance therapy aged 4 to 11 years with dosage adjustment.
Facilitates corticosteroid sparing by combining anti-inflammatory and bronchodilator effects.
Improves health-related quality of life for patients with obstructive airway diseases.
Decreases need for rescue inhaler usage by maintaining bronchodilation.
Recommended when prior asthma therapy with ICS or LABA alone is insufficient.
May be included in stepwise management plans for chronic asthma and COPD.

Side Or Adverse Effects

Oral and oropharyngeal candidiasis (thrush), requiring mouth rinsing after inhalation to reduce risk.
Dysphonia and hoarseness due to local corticosteroid effects.
Upper respiratory tract infections and inflammation including pharyngitis and sinusitis.
Bronchitis and cough as respiratory adverse effects.
Headache and nausea or vomiting reported with inhaler use.
Pneumonia in patients with COPD, with increased incidence in elderly patients (>65 years).
Throat irritation and viral respiratory infections notably in COPD patients.
Potential cardiovascular effects including tachycardia, palpitations, hypertension, and arrhythmias.
Local hypersensitivity reactions including rash, urticaria, angioedema, and bronchospasm.
Rare paradoxical bronchospasm immediately after inhalation requiring discontinuation.
Suppression of hypothalamic-pituitary-adrenal (HPA) axis at higher or prolonged doses causing adrenal insufficiency.
Reduction in bone mineral density with long-term use, particularly in patients with risk factors for osteoporosis.
Slowed growth velocity in pediatric patients on prolonged inhaled corticosteroids.
Glaucoma and cataracts observed with long-term inhaled corticosteroid therapy.
Eosinophilic conditions and rare cases resembling Churg-Strauss syndrome.
Gastrointestinal discomfort including diarrhea and abdominal pain.
Musculoskeletal pain, cramps, and rare fractures reported.
Nervous system effects such as tremor, nervousness, and insomnia.
Rare psychiatric disturbances including agitation and behavioral changes, especially in children.

Precautions

Not indicated for relief of acute bronchospasm or acute asthma/COPD exacerbations; a short-acting beta2-agonist should be used instead for acute symptoms.
Use caution in patients with cardiovascular disorders such as coronary insufficiency, arrhythmias, and hypertension due to potential beta2-agonist effects.
Monitor for signs of pneumonia in COPD patients due to increased risk with inhaled corticosteroids.
Rinse mouth after inhalation to minimize risk of oropharyngeal candidiasis.
Avoid use in patients with severe hypersensitivity to milk proteins due to lactose excipient.
Careful withdrawal and tapering recommended when switching from systemic corticosteroids to avoid adrenal insufficiency.
Use with caution in patients with infections such as tuberculosis, fungal, bacterial, viral, or parasitic infections due to immunosuppressive effects.
Monitor growth velocity in pediatric patients; titrate to lowest effective dose.
Be alert for immediate hypersensitivity reactions; discontinue if anaphylaxis or angioedema occurs.
Avoid concomitant use with other LABA-containing products to prevent overdose and increased adverse cardiovascular effects.
Monitor bone mineral density periodically in patients at risk for osteoporosis.
Exercise caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis.
Inform patients about potential effects on eye pressure and vision; ophthalmologic evaluation may be necessary.
Use caution when administering strong CYP3A4 inhibitors concomitantly due to risk of increased systemic corticosteroid exposure and adverse effects.
Advise patients to avoid exposure to chickenpox or measles and to inform healthcare provider if exposure occurs.

Warnings

LABA monotherapy increases the risk of serious asthma-related events, including death; Wixela Inhub should always be used in combination with an inhaled corticosteroid.
Wixela Inhub must not be initiated in acutely deteriorating asthma or COPD or used for acute symptom relief.
Concomitant use with other LABA-containing medicines is contraindicated due to overdose risks.
Patients should be instructed to rinse their mouth after inhalation to reduce oropharyngeal candidiasis risk.
An increased risk of pneumonia has been observed in COPD patients treated with Wixela Inhub, especially in adults over 65 years of age.
Potential worsening of existing infections, including tuberculosis and ocular herpes simplex; usage requires caution.
Risk of adrenal insufficiency and systemic corticosteroid effects during and after transition from systemic corticosteroid therapy.
Hypercorticism and adrenal suppression may develop, especially at higher doses or susceptible patients.
Paradoxical bronchospasm, which can be life-threatening, requires immediate discontinuation if it occurs.
Immediate hypersensitivity reactions, including anaphylaxis, may occur; especially a concern in patients with severe milk protein allergy.
Cardiovascular and CNS effects such as seizures, arrhythmias, hypertension or hypotension, tachycardia, nervousness, headaches, tremor, and insomnia may arise from beta-adrenergic stimulation.
Monitoring for reduction in bone mineral density and evidence of osteoporosis is recommended during long-term therapy.
Reduced growth velocity in pediatric patients; growth should be monitored regularly.
Long-term corticosteroid use may cause glaucoma, cataracts, or increased intraocular pressure; ophthalmologic referrals advised when warranted.
Patients must be warned about potential hypokalemia and hyperglycemia induced by beta2-agonists, especially in predisposed individuals.

Contraindication

Primary treatment of status asthmaticus or acute asthma/COPD episodes requiring intensive intervention.
Severe hypersensitivity to milk proteins contained in the lactose excipient of the inhalation powder.
Known hypersensitivity to fluticasone propionate, salmeterol, or any excipients contained in Wixela Inhub.
Concurrent use with other long-acting beta2-agonist medications for any reason.
Patients with life-threatening asthma excluded from clinical trials and should not use Wixela Inhub.
Use during acutely deteriorating asthma or COPD episodes.
Known history of immediate hypersensitivity reactions to the drug components.
Use in patients with severe milk protein allergy is specifically contraindicated due to lactose content.

Drug Interactions

Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir, ketoconazole, clarithromycin) are not recommended due to increased systemic exposure leading to risk of corticosteroid and cardiovascular adverse effects.
Ritonavir coadministration significantly increases fluticasone propionate plasma levels and decreases serum cortisol concentrations potentially causing Cushing’s syndrome and adrenal suppression.
Ketoconazole raises plasma exposure to both fluticasone propionate and salmeterol, with significant increases in salmeterol AUC and QTc interval prolongation observed.
Monoamine oxidase inhibitors and tricyclic antidepressants potentiate cardiovascular effects of salmeterol; extreme caution required with coadministration or within two weeks of discontinuation.
Beta-blockers may antagonize bronchodilator effects of salmeterol and can precipitate severe bronchospasm in asthma or COPD patients; cardioselective beta-blockers may be considered with caution.
Non–potassium-sparing diuretics (e.g., thiazides, loop diuretics) combined with beta-agonists may exacerbate hypokalemia and ECG changes.
Concomitant use with other sympathomimetic drugs may increase risk of cardiovascular adverse events.
Concurrent methylxanthine use (e.g., theophylline, aminophylline) has not shown altered adverse event profiles in controlled studies but should be monitored.
No significant drug interaction with intranasal corticosteroids or short-acting beta2-agonists has been reported.
Fluticasone propionate nasal spray concurrent use did not alter systemic exposure or adverse event rates.
No formal drug interaction studies performed with Wixela Inhub as a combination product, but individual components have known interactions.
CYP3A4 moderate inhibitors such as erythromycin may mildly increase salmeterol plasma concentrations, necessitating vigilance.

Preparations Of The Drug

Wixela Inhub inhalation powder containing fluticasone propionate and salmeterol xinafoate (equivalent to salmeterol base).
Available strengths: 100/50 mcg, 250/50 mcg, and 500/50 mcg per inhalation dose.
Each inhaler is a disposable grey plastic device containing two foil-sealed discs with 60 pre-metered doses in total.
Inactive ingredient includes lactose monohydrate, which contains milk proteins.
Supplied in moisture-protective foil pouches; to be stored sealed until use to maintain dose stability.
Storage recommended at controlled room temperature of 20° to 25°C (68° to 77°F) away from direct heat and sunlight.
Discard inhaler one month after opening the foil pouch or after the dose counter reads zero, whichever occurs first.
Manufactured by McDermott Laboratories Ltd., Ireland; marketed by Mylan Pharmaceuticals Inc.
Inhaler designed for oral inhalation only; not intended for use with spacer devices or aqueous nebulization.
Package includes patient information leaflet and detailed instructions for use with visual aids.
Available under FDA-approved ANDA applications since February 2019.
Supplied in cartons with one inhaler per carton.