Fluticasone Propionate and Salmeterol

5 WARNINGS AND PRECAUTIONS LABA monotherapy increases the risk of serious asthma-related events. ( 5.1 ) Deterioration of asthma and acute episodes: Do not use for relief of acute symptoms. Patients require immediate re-evaluation during rapidly deteriorating asthma. ( 5.2 ) Do not use in combination with an additional medicine containing LABA because of risk of overdose. ( 5.3 ) Localized infections: 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 ) Immunosuppression: Potential worsening of existing tuberculosis, fungal, bacterial, viral, parasitic infection, or 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. ( 5.5 ) Transferring patients from systemic corticosteroids: Risk of impaired adrenal function when transferring from systemic corticosteroids. Taper patients slowly from systemic corticosteroids if transferring to Fluticasone Propionate/Salmeterol. ( 5.6 ) 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/Salmeterol slowly. ( 5.7 ) Paradoxical bronchospasm: Discontinue Fluticasone Propionate/Salmeterol and institute alternative therapy if paradoxical bronchospasm occurs. ( 5.9 ) Use with caution in patients with cardiovascular or central nervous system disorders because of beta adrenergic stimulation. ( 5.11 ) Decreases in bone mineral density: Monitor patients with major risk factors for decreased bone mineral content. ( 5.12 ) Monitor growth of pediatric patients. ( 5.13 ) Close monitoring for glaucoma and cataracts is warranted. ( 5.14 ) Be alert to eosinophilic conditions, hypokalemia, and hyperglycemia. ( 5.15 , 5.17 ) Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis. ( 5.16 ) 5.1 Serious Asthma-Related Events – Hospitalizations, Intubations, Death Use of LABA as monotherapy [without inhaled corticosteroids (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 large, 26-week, randomized, blinded, 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 budesonide/formoterol to budesonide, 1 trial compared fluticasone propionate/salmeterol inhalation powder to fluticasone propionate inhalation powder, and 1 trial compared mometasone furoate/formoterol to mometasone furoate. The fourth trial included pediatric subjects aged 4 to 11 years and compared fluticasone propionate/salmeterol inhalation powder to fluticasone propionate inhalation powder. 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 116 105 1.10 (0.85, 1.44) Asthma-related death 2 0 Asthma-related intubation (endotracheal) 1 2 Asthma-related hospitalization (≥24-hour stay) 115 105 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 events 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. The pediatric safety trial included 6,208 pediatric patients aged 4 to 11 years who received ICS/LABA (fluticasone propionate/salmeterol inhalation powder) or ICS (fluticasone propionate inhalation powder). In this trial 27/3,107 (0.9%) of patients treated with ICS/LABA and 21/3,101 (0.7%) of patients treated with ICS experienced a serious asthma‑related event. There were no asthma-related deaths or intubations. ICS/LABA did not show a significantly increased risk of a serious asthma-related event compared to ICS based on the prespecified risk margin (2.7), with an estimated hazard ratio of time to first event of 1.29 (95% CI: 0.73, 2.27). Salmeterol Multicenter Asthma Research Trial (SMART) A 28-week, placebo-controlled, U.S. trial that compared the safety of salmeterol with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in subjects receiving salmeterol (13/13,176 in subjects treated with salmeterol versus 3/13,179 in subjects treated with placebo; relative risk: 4.37 [95% CI: 1.25, 15.34]). Use of background ICS was not required in SMART. The increased risk of asthma‑related death is considered a class effect of LABA monotherapy. 5.2 Deterioration of Disease and Acute Episodes Fluticasone Propionate/Salmeterol MDPI should not be initiated in patients during rapidly deteriorating or potentially life‑threatening episodes of asthma. Fluticasone Propionate/Salmeterol MDPI has not been studied in subjects with acutely deteriorating asthma. The initiation of Fluticasone Propionate/Salmeterol MDPI in this setting is not appropriate. Serious acute respiratory events, including fatalities, have been reported when salmeterol, a component of this product, has been initiated in patients with significantly worsening or acutely deteriorating asthma. In most cases, these have occurred in patients with severe asthma (e.g., patients with a history of corticosteroid dependence, low pulmonary function, intubation, mechanical ventilation, frequent hospitalizations, previous life‑threatening acute asthma exacerbations) and in some patients with acutely deteriorating asthma (e.g., patients with significantly increasing symptoms; increasing need for inhaled, short‑acting beta 2 ‑agonists; decreasing response to usual medications; increasing need for systemic corticosteroids; recent emergency room visits; deteriorating lung function). However, these events have occurred in a few patients with less severe asthma as well. It was not possible from these reports to determine whether salmeterol contributed to these events. Increasing use of inhaled, short‑acting beta 2 ‑agonists is a marker of deteriorating asthma. In this situation, the patient requires immediate reevaluation with reassessment of the treatment regimen, giving special consideration to the possible need for replacing the current strength of Fluticasone Propionate/Salmeterol MDPI with a higher strength, adding additional inhaled corticosteroid, or initiating systemic corticosteroids. Patients should not use more than 1 inhalation twice daily of Fluticasone Propionate/Salmeterol MDPI. Fluticasone Propionate/Salmeterol MDPI should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. An inhaled, short‑acting beta 2 ‑agonist, not Fluticasone Propionate/Salmeterol MDPI, should be used to relieve acute symptoms such as shortness of breath. When prescribing Fluticasone Propionate/Salmeterol MDPI, the healthcare provider should also prescribe an inhaled, short‑acting beta 2 -agonist (e.g., albuterol) for treatment of acute symptoms, despite regular twice‑daily use of Fluticasone Propionate/Salmeterol MDPI. When beginning treatment with Fluticasone Propionate/Salmeterol MDPI, patients who have been taking oral or inhaled, short‑acting beta 2 ‑agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs. 5.3 Avoid Excessive Use of Fluticasone Propionate/Salmeterol and Avoid Use with Other Long-Acting Beta 2 -Agonists Fluticasone Propionate/Salmeterol MDPI should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines containing LABA, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using Fluticasone Propionate/Salmeterol MDPI should not use another medicine containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason. 5.4 Oropharyngeal Candidiasis In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in subjects treated with Fluticasone Propionate/Salmeterol MDPI. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while treatment with Fluticasone Propionate/Salmeterol MDPI continues, but at times therapy with Fluticasone Propionate/Salmeterol MDPI may need to be interrupted. Advise the patient to rinse his/her mouth with water without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis. 5.5 Immunosuppression and Risk of Infections Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible adolescents or adults using corticosteroids. In such patients who have not had these diseases or who have not been properly immunized, particular care should be taken to avoid exposure. How the dose, route and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If a patient is exposed to chickenpox, prophylaxis with varicella-zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG) may be indicated. If a patient is 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 chickenpox develops, treatment with antiviral agents may be considered. Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. 5.6 Transferring Patients from Systemic Corticosteroid Therapy HPA Suppression/Adrenal Insufficiency Particular care is needed for patients who are transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic‑pituitary‑adrenal (HPA) function. Patients who have been previously maintained on 20 mg or more of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although Fluticasone Propionate/Salmeterol MDPI may improve control of asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of corticosteroid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies. During periods of stress or a severe asthmatic attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physician for further instruction. These patients should also be instructed to carry a medical identification warning card indicating that they may need supplementary systemic corticosteroids during periods of stress or a severe asthma attack. Patients requiring systemic corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to Fluticasone Propionate/Salmeterol MDPI. Lung function (mean forced expiratory volume in 1 second [FEV 1 ] or morning peak expiratory flow [AM PEF]), beta‑agonist use, and asthma symptoms should be carefully monitored during withdrawal of systemic corticosteroids. In addition to monitoring asthma signs and symptoms, patients should be observed for signs and symptoms of adrenal insufficiency, such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension. Unmasking of Allergic Conditions Previously Suppressed by Systemic Corticosteroids Transfer of patients from systemic corticosteroid therapy to Fluticasone Propionate/Salmeterol MDPI may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions). Corticosteroid Withdrawal Symptoms During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, depression) despite maintenance or even improvement of respiratory function. 5.7 Hypercorticism and Adrenal Suppression Fluticasone propionate, a component of Fluticasone Propionate/Salmeterol MDPI, will often help control asthma symptoms with less suppression of HPA function than therapeutically equivalent oral doses of prednisone. Since fluticasone propionate is absorbed into the circulation and can be systemically active at higher doses, the beneficial effects of Fluticasone Propionate/Salmeterol MDPI in minimizing HPA dysfunction may be expected only when recommended dosages are not exceeded and individual patients are titrated to the lowest effective dose. A relationship between plasma levels of fluticasone propionate and inhibitory effects on stimulated cortisol production has been shown after 4 weeks of treatment with fluticasone propionate inhalation aerosol. Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing Fluticasone Propionate/Salmeterol MDPI. Because of the possibility of significant systemic absorption of inhaled corticosteroids, patients treated with Fluticasone Propionate/Salmeterol MDPI should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response. It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients who are sensitive to these effects. If such effects occur, Fluticasone Propionate/Salmeterol MDPI should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids, and for management of asthma symptoms. 5.8 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors The use of strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with Fluticasone Propionate/Salmeterol MDPI is not recommended because increased systemic corticosteroid and increased cardiovascular adverse effects may occur [see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.3 )]. 5.9 Paradoxical Bronchospasm and Upper Airway Symptoms As with other inhaled medicines, Fluticasone Propionate/Salmeterol MDPI can produce paradoxical bronchospasm, which may be life‑threatening. If paradoxical bronchospasm occurs following dosing with inhaled fluticasone propionate/salmeterol medicines, it should be treated immediately with an inhaled, short-acting bronchodilator; inhaled fluticasone propionate/salmeterol medicines should be discontinued immediately; and alternative therapy should be instituted. Upper airway symptoms of laryngeal spasm, irritation, or swelling, such as stridor and choking, have been reported in patients receiving inhaled fluticasone propionate/salmeterol medicines. 5.10 Hypersensitivity Reactions, Including Anaphylaxis Immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur after administration of Fluticasone Propionate/Salmeterol MDPI. There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of other powder products containing lactose; therefore, patients with severe milk protein allergy should not use Fluticasone Propionate/Salmeterol MDPI [see Contraindications ( 4 )]. 5.11 Cardiovascular and Central Nervous System Effects Excessive beta‑adrenergic stimulation has been associated with seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, palpitation, nausea, dizziness, fatigue, malaise, and insomnia [see Overdosage ]. Therefore, Fluticasone Propionate/Salmeterol MDPI, like all products containing sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. Salmeterol, a component of Fluticasone Propionate/Salmeterol MDPI, can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of salmeterol at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta‑agonists have been reported to produce electrocardiogram (ECG) changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Large doses of inhaled or oral salmeterol (12 to 20 times the recommended dose) have been associated with clinically significant prolongation of the QTc interval, which has the potential for producing ventricular arrhythmias. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. 5.12 Reduction in Bone Mineral Density Decreases in bone mineral density (BMD) have been observed with long‑term administration of products containing inhaled corticosteroids. The clinical significance of small changes in BMD with regard to long‑term consequences such as fracture is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care. 5.13 Effect on Growth Orally inhaled corticosteroids, including Fluticasone Propionate/Salmeterol MDPI, may cause a reduction in growth velocity when administered to pediatric patients. Monitor the growth of pediatric patients receiving Fluticasone Propionate/Salmeterol MDPI routinely (e.g., via stadiometry). To minimize the systemic effects of orally inhaled corticosteroids, including Fluticasone Propionate/Salmeterol MDPI, titrate each patient’s dosage to the lowest dosage that effectively controls his/her symptoms [see Dosage and Administration ( 2 ), Use in Specific Populations ( 8.4 )] . 5.14 Glaucoma and Cataracts Glaucoma, increased intraocular pressure, and cataracts have been reported in patients following the long-term administration of inhaled corticosteroids, including fluticasone propionate, a component of Fluticasone Propionate/Salmeterol MDPI. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts. Effects of treatment with other fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg, fluticasone propionate 500 mcg, salmeterol 50 mcg, or placebo on development of cataracts or glaucoma was evaluated in a subset of 658 subjects with COPD in the 3-year survival trial. Ophthalmic examinations were conducted at baseline and at 48, 108, and 158 weeks. Conclusions about cataracts cannot be drawn from this trial because the high incidence of cataracts at baseline (61% to 71%) resulted in an inadequate number of subjects treated with other fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg who were eligible and available for evaluation of cataracts at the end of the trial (n = 53). The incidence of newly diagnosed glaucoma was 2% with other fluticasone propionate and salmeterol inhalation powder 500 mcg/50 mcg, 5% with fluticasone propionate, 0% with salmeterol, and 2% with placebo. 5.15 Eosinophilic Conditions and Churg-Strauss Syndrome In rare cases, patients on inhaled fluticasone propionate, a component of Fluticasone Propionate/Salmeterol MDPI, may present with systemic eosinophilic conditions. Some of these patients have clinical features of vasculitis consistent with Churg‑Strauss syndrome, a condition that is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of fluticasone propionate. Cases of serious eosinophilic conditions have also been reported with other inhaled corticosteroids in this clinical setting. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal relationship between fluticasone propionate and these underlying conditions has not been established. 5.16 Coexisting Conditions Fluticasone Propionate/Salmeterol MDPI, like all medicines containing sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis and in those who are unusually responsive to sympathomimetic amines. Doses of the related beta 2 ‑adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. 5.17 Hypokalemia and Hyperglycemia Beta‑adrenergic agonist medicines may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects [see Clinical Pharmacology ( 12.2 )] . The decrease in serum potassium is usually transient, not requiring supplementation. Clinically significant changes in blood glucose and/or serum potassium were seen infrequently during clinical trials with Fluticasone Propionate/Salmeterol MDPI at recommended doses.