Wixela Inhub

— THERAPEUTIC CATEGORIES —
  • Asthma/COPD
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Wixela Inhub Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Fluticasone propionate, salmeterol; 100mcg/50mcg, 250mcg/50mcg, 500mcg/50mcg; per inh; dry pwd for inh.

    Pharmacological Class

    Corticosteroid + long-acting beta-2 agonist (LABA).

    How Supplied

    Inhaler—1 (60 metered doses)

    How Supplied

    Wixela Inhub® 100/50, 250/50, and 500/50 are supplied in a carton containing one disposable grey colored plastic dry powder inhaler with two foil sealed discs, providing a total of 60 pre-metered doses.

    Storage

    Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature]. Store in a dry place away from direct heat and sunlight.

    Manufacturer

    Mylan Inc.

    Generic Availability

    NO

    Mechanism of Action

    Fluticasone propionate is a synthetic trifluorinated corticosteroid with anti-inflammatory activity. Corticosteroids have been shown to have a wide range of actions on multiple cell types (eg, mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (eg, histamine, eicosanoids, leukotrienes, cytokines) involved in inflammation. These anti-inflammatory actions of corticosteroids contribute to their efficacy in asthma.

    Salmeterol is a selective LABA. 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.

    Wixela Inhub Indications

    Indications

    Treatment of asthma in patients not adequately controlled on a long-term asthma control medication [eg, inhaled corticosteroid (ICS)] or whose disease warrants initiation of both an ICS and LABA. For 250mcg/50mcg only: maintenance treatment of COPD, including chronic bronchitis and/or emphysema. To reduce exacerbations of COPD in patients with a history of exacerbations.

    Limitations of Use

    Not for relief of acute bronchospasm.

    Wixela Inhub Dosage and Administration

    Adult

    Allow approx. 12hrs between doses. Asthma: ≥12yrs: initially 1 inh of 100/50 or 250/50 or 500/50 twice daily, based on disease severity and previous asthma therapy. If insufficient response after 2wks, use next higher strength. Max 1 inh of 500/50 twice daily. COPD: 1 inh of 250/50 twice daily. Rinse mouth after use.

    Children

    <4yrs: not established. Allow approximately 12hrs between doses. Asthma: 4–11yrs: 1 inh of 100/50 twice daily. Rinse mouth after use.

    Wixela Inhub Contraindications

    Contraindications

    Primary treatment of status asthmaticus or other acute episodes of asthma or COPD requiring intensive measures. Severe hypersensitivity to milk protein.

    Wixela Inhub Boxed Warnings

    Not Applicable

    Wixela Inhub Warnings/Precautions

    Warnings/Precautions

    LABA monotherapy (without ICS) may increase risk of asthma-related events (death, hospitalizations, intubations). Do not initiate in rapidly or acutely deteriorating COPD or asthma. Not for use with other long-acting β2-agonists. Do not exceed recommended dose. Prescribe a short-acting, inhaled β2-agonist for acute symptoms; monitor for increased need. Monitor for signs/symptoms of pneumonia. Immunosuppressed. Tuberculosis. Systemic infections. Ocular herpes simplex. If exposed to chickenpox or measles, consider immune globulin prophylaxis or antiviral ­treatment. Monitor for adrenal insufficiency when transferring from systemic steroids. May need supplemental systemic corticosteroids during periods of stress or a severe asthma attack. May unmask previously suppressed allergic conditions. Reevaluate periodically. Monitor for hypercorticism and HPA axis suppression (if occurs, discontinue gradually), growth in children, IOP, glaucoma, or cataracts. Consider eye exams if ocular symptoms develop or in long-term use. Discontinue and treat if paradoxical bronchospasm occurs; use alternative therapy. Cardiovascular disease (esp. coronary insufficiency, arrhythmias, hypertension). Eosinophilic conditions. Convulsive disorders. Thyrotoxicosis. Hyperresponsiveness to sympathomimetics. Diabetes. Ketoacidosis. Hypokalemia. Hyperglycemia. Hepatic impairment; monitor. Assess bone mineral density if risk factors exist (eg, prolonged immobilization, osteoporosis, postmenopausal, advanced age, others). Labor & delivery. Pregnancy: monitor. Nursing mothers.

    Warnings/Precautions

    Serious Asthma-Related Events – Hospitalizations, Intubations and Death

    • Increased risk for asthma-related death when use of LABA as monotherapy (without ICS) for asthma. Moreover, use of LABA as monotherapy increases the risk for asthma-related hospitalization in pediatric and adolescent patients.

    Serious Asthma-Related Events with ICS/LABA

    • Four large, 26-week, clinical safety trials evaluated the risk for serious asthma-related events when LABA were used in fixed-dose combination with ICS vs ICS alone in patients with asthma. 

      • In the 3 adult and adolescent trials, ICS/LABA met its pre-specified objective and demonstrated noninferiority to ICS alone. A meta-analysis of the 3 trials did not show a significant increase in risk for a serious asthma-related event with ICS/LABA fixed-dose combination vs ICS alone.

      • In the pediatric safety trial, there were no asthma-related deaths or intubations. ICS/LABA did not show a significantly increased risk for a serious asthma-related event vs ICS.

    Salmeterol Multicenter Asthma Research Trial (SMART)

    • In a 28-week, placebo-controlled US trial, the safety of salmeterol was compared with placebo in addition to the usual asthma therapy. Findings showed an increase in asthma-related deaths among patients-treated with salmeterol. The use of background ICS was not required in this trial.

    Deterioration of Disease and Acute Asthma Episodes

    • Do not initiate Wixela Inhub in patients during rapidly deteriorating or potentially life-threatening episodes of asthma or COPD. Wixela Inhub has not been studied in patients with acutely deteriorating asthma or COPD.

    • A marker of deteriorating asthma is an increased use of inhaled, short-acting beta2-agonists; immediately re-evaluate patient if this occurs.

    • Do not use Wixela Inhub for the relief of acute symptoms (eg, as rescue therapy for the treatment of acute episodes of bronchospasm.

    • When beginning treatment with Wixela Inhub, patients who have been taking oral or inhaled, short-acting beta2-agonists on a regular basis (eg, 4 times a day) should be instructed to discontinue the regular use of these drugs.

    Excessive Use of Wixela Inhub and Use with Other Long-Acting Beta2-Agonists

    • Do not use more often than the recommended, at higher doses than recommended, or in conjunction with other medications containing LABA.

    • Do not use an additional LABA for any reason, including prevention of exercise-induced bronchospasm or the treatment of asthma or COPD.

    Local Effects of Inhaled Corticosteroids

    • Localized infections with Candida albicans may occur in the mouth and pharynx in some patients.

    • If these infections develop, patients may require treatment with appropriate local or systemic antifungal therapy and/or interruption of treatment.

    • Rinse mouth after each inhalation. 

    Pneumonia 

    • Risk for development of pneumonia in patients with COPD as the clinical features of pneumonia and exacerbations frequently overlap.

    Immunosuppression

    • If exposed to chickenpox, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated.

    • If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated (see the respective package inserts for complete VZIG and IG prescribing information).

    • If chicken pox develops, may consider treatment with antiviral agents.

    • Use caution in patients with active or quiescent tuberculosis infection of the respiratory tract, untreated systemic fungal, bacterial, viral or parasitic infections; or ocular herpes simplex. 

    Transferring Patients from Systemic Corticosteroid Therapy

    • Use particular care when transferring patients from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency may occur.

    • The most susceptible patients are those who have been previously maintained on 20 mg or more per day of prednisone (or its equivalent).

    • A number of months are required for recovery of HPA-axis function after withdrawal from systemic corticosteroids. During this period of HPA-axis suppression, patients exposed to trauma, surgery, infection, or other conditions associated with severe electrolyte loss may exhibit signs and symptoms of adrenal insufficiency.

    • During periods of stress, a severe COPD exacerbation, or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and contact their physicians. These patients should carry a medical identification card.

    • If oral corticosteroids are required, patients should be weaned slowly from systemic corticosteroid use after transferring to Wixela Inhub. For these patients, accomplish prednisone reduction by reducing the daily prednisone dose by 2.5mg on a weekly basis during Wixela Inhub therapy. Monitor carefully lung function (FEV1 or AM PEF), beta-agonist use, and asthma or COPD symptoms during withdrawal of oral corticosteroids. Observe for signs and symptoms of adrenal insufficiency.

    • Transfer from systemic corticosteroid therapy to Wixela Inhub may unmask conditions previously suppressed by the systemic corticosteroid therapy.

    Hypercorticism and Adrenal Suppression  

    • Use particular care when observing patients post-operatively or during periods of stress for evidence of inadequate adrenal response

    • Systemic corticosteroid effects may occur, including hypercorticism, and adrenal suppression (including adrenal crisis), particularly when ICS is administered at higher than recommended doses over prolonged periods of time. Reduce dose of Wixela Inhub slowly if these effects occur.

    Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors

    • Use caution when considering using ketoconazole and other known strong CYP3A4 inhibitors  (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) with Wixela Inhub because it may potentiate systemic exposure to systemic corticosteroid and increase the risk for cardiovascular adverse effects. 

    Paradoxical Bronchospasm and Upper Airway Symptoms 

    • Discontinue treatment and institute alternative therapy if paradoxical bronchospasm occurs, and treat immediately with a fast-acting inhaled bronchodilator.

    Immediate Hypersensitivity Reactions 

    • Immediate hypersensitivity reactions may occur, including urticaria, angioedema, rash, and bronchospasm. 

    Cardiovascular and Central Nervous System Effects

    • Use with caution in patients with cardiovascular disorders (esp. coronary insufficiency, arrhythmias, hypertension). Consider discontinuing treatment if significant cardiovascular effects occur.

    • Beta2-agonists can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic and/or diastolic blood pressure, and/or symptoms. ECG changes have also been reported.

    Reduction in Bone Mineral Density

    • Decreases in bone mineral density (BMD) have been observed with long-term administration of inhaled corticosteroids.

    • Monitor and treat appropriately in patients with major risk factors for decreased BMD, such as prolonged immobilization, family history of osteoporosis, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants and corticosteroids).

    Effects on Growth

    • May cause a reduction in growth velocity when administered to pediatric patients.

    • Monitor growth routinely if administered to pediatric patients. These systemic effects can be minimized by titrating each patient to their lowest effective dose.

    Glaucoma and Cataracts

    • Monitor closely in patients with a change in vision or with a history of increased  intraocular pressure, glaucoma, and/or cataracts.

    Eosinophilic Conditions and Churg-Strauss Syndrome 

    • In rare cases, may present with systemic eosinophilic conditions.

    • Health care providers should be alert to eosinophilia, vasculitis rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients.

    Coexisting Conditions

    • Use with caution in patients with convulsive disorders or thyrotoxicosis. Use with caution in patients who are unusually responsive to sympathomimetic amines.

    • Doses of the related beta2-agonist albuterol, when given intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. 

    Hypokalemia and Hyperglycemia

    • Beta-agonists may produce significant hypokalemia in some patients.

    • This is usually transient and does not require supplementation.

    Pregnancy Considerations

    Risk Summary

    • Insufficient data on the use of fluticasone propionate and salmeterol inhalation powder or individual monoproducts, fluticasone propionate and salmeterol xinafoate, in pregnant women.

    Clinical Considerations

    • Disease-Associated Maternal and/or Embryofetal Risk: Pregnant women should be closely monitored and medication adjusted as necessary to maintain optimal control of asthma. 

    • Labor or Delivery: Use only during labor if the potential benefit justifies the potential for risks related to beta-agonists interfering with uterine contractility.

    Nursing Mother Considerations

    Risk Summary

    • There is no available data on the effects of fluticasone propionate or salmeterol on the breastfed child or the effects on milk production. 

    • Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for Wixela Inhub and any potential adverse effects on the breastfed child from Wixela Inhub or from the underlying maternal condition. 

    Pediatric Considerations

    • The safety and effectiveness of fluticasone propionate and salmeterol inhalation powder in asthma patients less than 4 years of age have not been established.

    • May cause a reduction in growth velocity when administered to pediatric patients.

    • Monitor growth routinely if administered to pediatric patients. These systemic effects can be minimized by titrating each patient to their lowest effective dose.

    Geriatric Considerations

    No adjustment of the dosage of Wixela Inhub in geriatric patients is necessary, but greater sensitivity in some older individuals cannot be ruled out. 

    Renal Impairment Considerations

    Formal pharmacokinetic studies have not been conducted in patients with renal impairment.

    Hepatic Impairment Considerations

    • Formal pharmacokinetic studies have not been conducted in patients with hepatic impairment.

    • Hepatic impairment may lead to accumulation of fluticasone propionate and salmeterol in plasma. Monitor closely in patients with hepatic disease.

    Wixela Inhub Pharmacokinetics

    Distribution

    Fluticasone Propionate: Following intravenous administration, the initial disposition phase for fluticasone propionate was rapid and consistent with its high lipid solubility and tissue binding. The volume of distribution averaged 4.2 L/kg. 

    The percentage of fluticasone propionate bound to human plasma proteins averages 99%. Fluticasone propionate is weakly and reversibly bound to erythrocytes and is not significantly bound to human transcortin. 

    Salmeterol: The percentage of salmeterol bound to human plasma proteins averages 96% in vitro over the concentration range of 8 to 7,722 ng of salmeterol base per milliliter, much higher concentrations than those achieved following therapeutic doses of salmeterol. 

    Metabolism

    Fluticasone Propionate: The only circulating metabolite detected in man is the 17β-carboxylic acid derivative of fluticasone propionate, which is formed through the CYP3A4 pathway.

    Salmeterol: Salmeterol base is extensively metabolized by hydroxylation, with subsequent elimination predominantly in the feces. No significant amount of unchanged salmeterol base was detected in either urine or feces.  

    Elimination

    Fluticasone Propionate: Following intravenous dosing, fluticasone propionate showed polyexponential kinetics and had a terminal elimination half-life of approximately 7.8 hours. Less than 5% of a radiolabeled oral dose was excreted in the urine as metabolites, with the remainder excreted in the feces as parent drug and metabolites. Terminal half-life estimates of fluticasone propionate for Wixela Inhub averaged 5.6 hours. 

    Salmeterol: In 2 healthy adult subjects who received 1 mg of radiolabeled salmeterol (as salmeterol xinafoate) orally, approximately 25% and 60% of the radiolabeled salmeterol was eliminated in urine and feces, respectively, over a period of 7 days. The terminal elimination half-life was about 5.5 hours (1 volunteer only). 

    The xinafoate moiety has no apparent pharmacologic activity. 

    The xinafoate moiety is highly protein bound (>99%) and has a long elimination half-life of 11 days. No terminal half-life estimates were calculated for salmeterol following administration of Wixela Inhub. 

    Wixela Inhub Interactions

    Interactions

    Concomitant strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, ritonavir, atazanavir, clarithromycin, indinavir, nefazodone, nelfinavir, saquinavir, telithromycin): not recommended. Caution during or within 2 weeks of discontinuing MAOIs or tricyclic antidepressants, β-blockers (consider cardioselective), K+-depleting diuretics.

    Wixela Inhub Adverse Reactions

    Adverse Reactions

    Upper respiratory tract infection or inflammation, pharyngitis, dysphonia, oral candidiasis, bronchitis, cough, headache, nausea, vomiting, pneumonia, throat irritation, musculoskeletal pain; hypersensitivity reactions, cardiovascular or CNS effects.

    Wixela Inhub Clinical Trials

    Clinical Trials

    ASTHMA

    Three (3) double-blind, parallel-group clinical trials were conducted with Wixela Inhub in 1,208 adult and adolescent patients (aged 12 years and older, mean baseline FEV1 63% to 72% of predicted normal) with asthma that was not optimally controlled on their current therapy. All treatments were inhalation powders given as 1 inhalation from a dry powder twice daily, and other maintenance therapies were discontinued. 

    Trial 1: Clinical Trial with Fluticasone Propionate and Salmeterol Inhalation Powder 100 mcg/50 mcg

    This was a placebo-controlled, 12-week, US trial that compared fluticasone propionate and salmeterol inhalation powder 100 mcg/50 mcg. This trial was stratified according to baseline asthma therapy: patients using beta-agonists (albuterol alone or salmeterol) or ICS.

    Baseline FEV1 measurements were similar across treatments: fluticasone propionate and salmeterol inhalation powder 100 mcg/50 mcg, 2.17 L; fluticasone propionate 100 mcg, 2.11 L; salmeterol, 2.13 L; and placebo, 2.15 L. 

    Predefined withdrawal criteria for lack of efficacy, an indicator of worsening asthma, were utilized for this placebo-controlled trial.

    Results showed statistically significantly fewer patients who received fluticasone propionate and salmeterol inhalation powder 100 mcg/50 mcg were withdrawn due to worsening asthma compared with fluticasone propionate, salmeterol, and placebo. 

    The FEV1 results at endpoint showed that patients who received fluticasone propionate and salmeterol inhalation powder 100 mcg/50 mcg had significantly greater improvements in FEV1 (0.51 L, 25%) compared with fluticasone propionate 100 mcg (0.28 L, 15%), salmeterol (0.11 L, 5%), and placebo (0.01 L, 1%).

    The subjective impact of asthma on patients’ perception of health was evaluated through use of an instrument called the Asthma Quality of Life Questionnaire (AQLQ) (based on a 7-point scale where 1 = maximum impairment and 7 = none). Patients receiving fluticasone propionate and salmeterol inhalation powder 100 mcg/50 mcg had clinically meaningful improvements in overall asthma-specific quality of life as defined by a difference between groups of ≥0.5 points in change from baseline AQLQ scores (difference in AQLQ score of 1.25 compared with placebo).

     

    Trial 2: Clinical Trial with Fluticasone Propionate and Salmeterol Inhalation Powder 250 mcg/50 mcg 

    This placebo-controlled, 12-week, US trial compared fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg with its individual components, fluticasone propionate 250 mcg and salmeterol 50 mcg, in 349 subjects with asthma using ICS (daily doses of beclomethasone dipropionate 462 to 672 mcg; flunisolide 1,250 to 2,000 mcg; fluticasone propionate inhalation aerosol 440 mcg; or triamcinolone acetonide 1,100 to 1,600 mcg).

    Baseline FEV1 measurements were similar across treatments: fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg, 2.23 L; fluticasone propionate 250 mcg, 2.12 L; salmeterol, 2.20 L; and placebo, 2.19 L. 

    Efficacy results in this trial were similar to those observed in Trial 1. Patients who received fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg had significantly greater improvements in FEV1 (0.48 L, 23%) compared with fluticasone propionate 250 mcg (0.25 L, 13%), salmeterol (0.05 L, 4%), and placebo (decrease of 0.11 L, decrease of 5%). Statistically significantly fewer subjects receiving fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg were withdrawn from this trial for worsening asthma (4%) compared with fluticasone propionate (22%), salmeterol (38%), and placebo (62%). In addition, fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg was superior to fluticasone propionate, salmeterol, and placebo for improvements in morning and evening PEF. Subjects receiving fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg also had clinically meaningful improvements in overall asthma-specific quality of life as described in Trial 1 (difference in AQLQ score of 1.29 compared with placebo).

     

    Trial 3: Clinical Trial with Fluticasone Propionate and Salmeterol Inhalation Powder 500 mcg/50 mcg 

    This 28-week, non-US trial compared fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg with fluticasone propionate 500 mcg alone and concurrent therapy (salmeterol 50 mcg plus fluticasone propionate 500 mcg administered from separate inhalers) twice daily in 503 subjects with asthma using ICS (daily doses of beclomethasone dipropionate 1,260 to 1,680 mcg; budesonide 1,500 to 2,000 mcg; flunisolide 1,500 to 2,000 mcg; or fluticasone propionate inhalation aerosol 660 to 880 mcg [750 to 1,000 mcg inhalation powder]).

    The primary efficacy parameter, morning PEF, was collected daily for the first 12 weeks of the trial. The primary purpose of weeks 13 to 28 was to collect safety data. Baseline PEF measurements were similar across treatments: fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg, 359 L/min; fluticasone propionate 500 mcg, 351 L/min; and concurrent therapy, 345 L/min. 

    Results showed that the morning PEF improved significantly withfluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg compared with fluticasone propionate 500 mcg over the 12-week treatment period. Improvements in morning PEF observed with fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg were similar to improvements observed with concurrent therapy.

     

    Onset of Action and Progression of Improvement in Asthma Control

    The onset of action and progression of improvement in asthma control were evaluated in the 2 placebo-controlled U.S. trials. Following the first dose, the median time to onset of clinically significant bronchodilatation (≥15% improvement in FEV1) in most subjects was seen within 30 to 60 minutes. Maximum improvement in FEV1 generally occurred within 3 hours, and clinically significant improvement was maintained for 12 hours (Figure 2). 

    Following the initial dose, predose FEV1 relative to Day 1 baseline improved markedly over the first week of treatment and continued to improve over the 12 weeks of treatment in both trials. No diminution in the 12-hour bronchodilator effect was observed with either fluticasone propionate and salmeterol inhalation powder 100 mcg/50 mcg or fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg as assessed by FEV1 following 12 weeks of therapy.

     

    Pediatric Subjects

    A 12-week US trial compared fluticasone propionate and salmeterol inhalation powder 100 mcg/50 mcg twice daily with fluticasone propionate inhalation powder 100 mcg twice daily in 203 children with asthma aged 4 to 11 years. At trial entry, patients were symptomatic on low doses of ICS. Morning predose FEV1 was obtained at baseline and endpoint in children 6 to 11 years of age.

    Results showed that patients treated with fluticasone propionate and salmeterol inhalation powder 100 mcg/50 mcg achieved an increased FEV1 of 1.70 L at baseline (n = 79) to 1.88 L at Endpoint (n = 69) compared with an increase from 1.65 L at baseline (n = 83) to 1.77 L at Endpoint (n = 75) in patients treated with fluticasone propionate 100 mcg.

     

    Safety and Efficacy Trials Comparing Fluticasone Propionate and Salmeterol Inhalation Powder with Fluticasone Propionate: Serious Asthma-Related Events

    Two 26-week, randomized, double-blind, parallel-group, active comparator trials compared the safety and efficacy of fluticasone propionate and salmeterol inhalation powder with fluticasone propionate inhalation powder in adult and adolescent subjects (Trial 4, NCT01475721) and in pediatric subjects aged 4 to 11 years (Trial 5, NCT01462344). The primary safety objective of both trials was to evaluate whether the addition of salmeterol xinafoate to fluticasone propionate therapy (fluticasone propionate and salmeterol inhalation powder) was non-inferior to ICS fluticasone propionate in terms of the risk of a serious asthma-related event (hospitalization, endotracheal intubation, and death). 

    Trial 4 enrolled subjects with moderate to severe persistent asthma with a history of asthma-related hospitalization or at least 1 asthma exacerbation in the previous year treated with systemic corticosteroids. A total of 11,679 adult and adolescent subjects [5,834 receiving fluticasone propionate and salmeterol inhalation powder 100 mcg/50 mcg, fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg, or fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg and 5,845 receiving fluticasone propionate inhalation powder (100, 250, or 500 mcg)] were included. Trial 5 enrolled subjects with a diagnosis of asthma and a history of at least 1 asthma exacerbation in the previous year treated with systemic corticosteroid. A total of 6,208 subjects aged 4 to 11 years [3,107 receiving fluticasone propionate and salmeterol inhalation powder 100 mcg/50 mcg or fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg and 3,101 receiving fluticasone propionate inhalation powder (100 or 250 mcg)] were included. In both trials, subjects with life-threatening asthma were excluded. In Trials 4 and 5, fluticasone propionate and salmeterol inhalation powder was non-inferior to fluticasone propionate in terms of time to first serious asthma-related events based on the pre-specified risk margins, with estimated hazard ratios of 1.03 (95% CI: 0.64, 1.66) and 1.29 (95% CI: 0.73, 2.27), respectively.

     

    Safety and Efficacy Trials Comparing Fluticasone Propionate and Salmeterol Inhalation Powder with Fluticasone Propionate: Effect on Exacerbation

    Trials 4 and 5 included time to first exacerbation as a secondary endpoint, where exacerbation was defined as a deterioration of asthma requiring the use of systemic corticosteroids for at least 3 days or an in-patient hospitalization or emergency department visit due to asthma that required systemic corticosteroids. In Trials 4 and 5, the hazard ratio for the time to first asthma exacerbation for fluticasone propionate and salmeterol inhalation powder relative to fluticasone propionate inhalation powder was 0.79 (95% CI: 0.70, 0.89) and 0.86 (95% CI: 0.73, 1.01), respectively. The difference in exacerbations was primarily driven by a reduction in those requiring systemic corticosteroids only.

     

    CHRONIC OBSTRUCTIVE PULMONARY DISEASE

    The efficacy of fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg and fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg in the treatment of subjects with COPD was evaluated in 6 randomized, double-blind, parallel-group clinical trials in adult subjects aged 40 years and older. These trials were primarily designed to evaluate the efficacy of fluticasone propionate and salmeterol inhalation powder on lung function (3 trials), exacerbations (2 trials), and survival (1 trial).

     

    Lung Function

    The efficacy of fluticasone propionate and salmeterol inhalation powder on lung function was evaluated in 2 of the 3 clinical trials, which included 1414 patients with COPD associated with chronic bronchitis. In the 2 trials, all patients had a history of cough productive of sputum that was not attributable to another disease process on most days for at least 3 months of the year for at least 2 years.

     

    1 trial evaluated the efficacy of fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg compared with its components fluticasone propionate 250 mcg and salmeterol 50 mcg and with placebo, and the other trial evaluated the efficacy of fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg compared with its components fluticasone propionate 500 mcg and salmeterol 50 mcg and with placebo. Trial treatments were inhalation powders given as 1 inhalation from the dry powder inhaler twice daily.

    Results showed that fluticasone propionate and salmeterol inhalation powder achieved significant greater improvements in lung function (as defined by predose and postdose FEV1) compared with fluticasone propionate, salmeterol, or placebo. The improvement in lung function with fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg was similar to the improvement seen with fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg.

    Patients who received fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg had significantly greater improvements in predose FEV1 at Endpoint (165 mL, 17%) compared with salmeterol 50 mcg (91 mL, 9%) and placebo (1 mL, 1%), demonstrating the contribution of fluticasone propionate to the improvement in lung function with fluticasone propionate and salmeterol inhalation powder. Patients who received fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg had significantly greater improvements in postdose FEV1 at Endpoint (281 mL, 27%) compared with fluticasone propionate 250 mcg (147 mL, 14%) and placebo (58 mL, 6%), demonstrating the contribution of salmeterol to the improvement in lung function with fluticasone propionate and salmeterol inhalation powder.

     

    In the third 1-year trial, 1465 patients evaluated fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg, fluticasone propionate 500 mcg, salmeterol 50 mcg, and placebo. Patients had an established history of COPD and exacerbations, a pre-bronchodilator FEV1 <70% of predicted at trial entry, and 8.3% reversibility. Patients treated with fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg had greater improvements in FEV1 (113 mL, 10%) compared with fluticasone propionate 500 mcg (7 mL, 2%), salmeterol (15 mL, 2%), and placebo (-60 mL, -3%).

     

    Exacerbations

    The effect of fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg on exacerbations was evaluated in two trials. Exacerbations were defined as worsening of 2 or more major symptoms (dyspnea, sputum volume, and sputum purulence) or worsening of any 1 major symptom together with any 1 of the following minor symptoms: sore throat, colds (nasal discharge and/or nasal congestion), fever without other cause, and increased cough or wheeze for at least 2 consecutive days.

    Exacerbations were also evaluated as a secondary outcome in the 1- and 3-year trials with fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg. There was not a symptomatic definition of exacerbation in these 2 trials. Exacerbations were defined in terms of severity requiring treatment with antibiotics and/or systemic corticosteroids (moderately severe) or requiring hospitalization (severe).

     

    The 2 exacerbation trials with fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg were identical trials designed to evaluate the effect of fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg and salmeterol 50 mcg, each given twice daily, on exacerbations of COPD over a 12-month period. A total of 1579 patients had an established history of COPD (but no other significant respiratory disorders). All patients were treated with fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg twice daily during a 4-week run-in period prior to being assigned trial treatment with twice-daily fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg or salmeterol 50 mcg. 

    In both trials, a significantly lower annual rate of moderate/severe COPD exacerbations was observed in patients treated with fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg compared with salmeterol (30.5% reduction [95% CI: 17.0, 41.8], P < 0.001) in the first trial and (30.4% reduction [95% CI: 16.9, 41.7], P < 0.001) in the second trial. Moreover, a significantly lower annual rate of exacerbations requiring treatment with oral corticosteroids was observed in patients treated with fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg compared with patients treated with salmeterol (39.7% reduction [95% CI: 22.8, 52.9], P < 0.001) in the first trial and (34.3% reduction [95% CI: 18.6, 47.0], P < 0.001) in the second trial. Secondary endpoints including pulmonary function and symptom scores improved more in subjects treated with fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg than with salmeterol 50 mcg in both trials.

     

    Exacerbations were evaluated in the 1- and the 3-year trials with fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg as 1 of the secondary efficacy endpoints. In the 1-year trial, a significantly lower rate of moderate and severe exacerbations was observed in the fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg treatment arm compared with placebo (25.4% reduction compared with placebo [95% CI: 13.5, 35.7]) but not when compared with its components (7.5% reduction compared with fluticasone propionate [95% CI: -7.3, 20.3] and 7% reduction compared with salmeterol [95% CI: -8.0, 19.9]). In the 3-year trial, the fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg treatment arm had a significantly lower rate of moderate and severe exacerbations compared with each of the other treatment groups (25.1% reduction compared with placebo [95% CI: 18.6, 31.1], 9.0% reduction compared with fluticasone propionate [95% CI: 1.2, 16.2], and 12.2% reduction compared with salmeterol [95% CI: 4.6, 19.2]).

    Across trials, the reduction in exacerbations seen with fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg was not greater than the reduction in exacerbations seen with fluticasone propionate and salmeterol inhalation powder 250 mcg/50 mcg.

     

    Survival

    A 3-year multicenter, international trial evaluated the efficacy of fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg compared with fluticasone propionate 500 mcg, salmeterol 50 mcg, and placebo on survival in 6112 patients with COPD. Patients were permitted usual COPD therapy with the exception of other ICS and long-acting bronchodilators. The patients were aged 40 to 80 years with an established history of COPD, a pre-bronchodilator FEV1 <60% of predicted at trial entry, and <10% of predicted reversibility. Each subject who withdrew from double-blind treatment for any reason was followed for the full 3-year trial period to determine survival status. The primary efficacy endpoint was all-cause mortality. 

    Survival with fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg was not significantly improved compared with placebo or the individual components (all-cause mortality rate 12.6% fluticasone propionate and salmeterol inhalation powder versus 15.2% placebo). The rates for all-cause mortality were 13.5% and 16.0% in the groups treated with salmeterol 50 mcg and fluticasone propionate 500 mcg, respectively. Secondary outcomes, including pulmonary function (post-bronchodilator FEV1), improved with fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg, salmeterol 50 mcg, and fluticasone propionate 500 mcg compared with placebo.

    Wixela Inhub Note

    Not Applicable

    Wixela Inhub Patient Counseling

    Patient Counseling

    Serious Asthma-Related Events

    • Inform patients with asthma that LABA when used alone increases the risk of asthma-related hospitalization or asthma-related death. Available data show that when ICS and LABA are used together, such as with Wixela Inhub, there is not a significant increase in the risk of these events. 

    Not for Acute Symptoms

    • Inform patients that Wixela Inhub is not meant to relieve acute symptoms of asthma of COPD and extra doses should not be used for that purpose. Advise patients to treat acute symptoms with an inhaled, short-acting beta2-agonist such as albuterol. Provide patients with such medication and instruct them in how it should be used.

    • Instruct patients to seek medical attention immediately if they experience any of the following: decreasing effectiveness of inhaled, short-acting beta2-agonists; need for more inhalations than usual of inhaled, short-acting beta2-agonists; or significant decrease in lung function as outlined by the physician.

    • Tell patients they should not stop therapy with Wixela Inhub without physician/provider guidance since symptoms may recur after discontinuation.

    Do Not Use Additional Long-acting Beta2-agonists

    • Instruct patients not to use other LABA for asthma and COPD.

    Local Effects

    • Inform patients that localized infections with Candida albicans occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, treat it with appropriate local or systemic (ie, oral) antifungal therapy while still continuing therapy with Wixela Inhub, but at times therapy with Wixela Inhub may need to be temporarily interrupted under close medical supervision. Advise patients to rinse the mouth with water without swallowing after inhalation to help reduce the risk of thrush.

    Pneumonia

    • Patients with COPD have a higher risk of pneumonia; instruct them to contact their healthcare providers if they develop symptoms of pneumonia.

    Immunosuppression and Risk of Infections

    • Warn patients who are on immunosuppressant doses of corticosteroids to avoid exposure to chickenpox or measles and, if exposed, to consult their physicians without delay. Inform patients of potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.

    Hypercorticism and Adrenal Suppression

    • Advise patients that Wixela Inhub may cause systemic corticosteroid effects of hypercorticism and adrenal suppression. Additionally, inform patients that deaths due to adrenal insufficiency have occurred during and after transfer from systemic corticosteroids. Patients should taper slowly from systemic corticosteroids if transferring to Wixela Inhub.

    Reduction in Bone Mineral Density

    • Advise patients who are at an increased risk for decreased BMD that the use of corticosteroids may pose an additional risk. 

    Reduced Growth Velocity

    • Advise patients that orally inhaled corticosteroids may reduce growth velocity in pediatric patients. Physicians should closely monitor the growth of children and adolescents.

    Ocular Effects

    • Advise patients that long-term use of ICS may increase the risk of some eye problems (cataracts or glaucoma); consider regular eye examinations.

    Risks Associated with Beta-agonist Therapy

    • Inform patients of adverse effects associated with beta2-agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness.

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