salmeterol/fluticasone inhaled (Rx)

>10%

Upper respiratory tract infection (21-27%)

Headache (12-21%)

Pharyngitis (10-13%)

1-10%

Candidiasis, nonspecific site (0-10%)

Throat irritation (7-9%)

Musculoskeletal pain (2-9%)

Bronchitis (2-8%)

Upper respiratory inflammation (4-7%)

Viral respiratory infections (4-6%)

Nausea or vomiting (4-6%)

Cough (3-6%)

Sinusitis (4-5%)

Hoarseness or dysphonia (2-5%)

Fever (3-4%)

Diarrhea (2-4%)

Gastrointestinal (GI) discomfort or pain (1-4%)

Oral candidiasis (1-4%)

Muscle cramps or spasms (3%)

Malaise or fatigue (2-3%)

Viral GI infections (0-3%)

Postmarketing Reports

Cardiac: Arrhythmias, ventricular tachycardia

Endocrine: Cushing syndrome, cushingoid features, growth velocity reduction in children and adolescents, hyperadrenocorticism

Eye: Glaucoma, cataracts, blurred vision, and central serous chorioretinopathy

GI: Abdominal pain, dyspepsia, xerostomia

Immunologic: Immediate and delayed hypersensitivity reaction, anaphylactic reaction in patients with severe milk protein allergy (very rare)

Metabolic: Hyperglycemia, weight gain

Musculoskeletal: Arthralgia, cramps, myositis, osteoporosis

Neurologic: Paresthesia, restlessness

Psychiatric: Agitation, aggression, depression, behavioral changes (eg, hyperactivity, irritability; rare and occurring primarily in children)

Reproductive: Dysmenorrhea

Respiratory: Congestion, tightness, dyspnea, facial and oropharyngeal edema, immediate bronchospasm, paradoxical bronchospasm, tracheitis, wheezing, upper respiratory symptoms (eg, laryngeal spasm, irritation, or swelling, such as stridor or choking)

Dermatologic: Ecchymoses, photodermatitis

Vascular: Pallor

Contraindications

Primary treatment of status asthmaticus or acute episodes of asthma or COPD requiring intensive measures

Severe hypersensitivity to milk proteins or demonstrated hypersensitivity to fluticasone propionate, salmeterol, or any of the excipients

Cautions

Risk of LABAs used as monotherapy

• Use of LABAs as monotherapy (without inhaled corticosteroids [ICS]) for asthma is associated with an increased risk of asthma-related death
• Data from controlled clinical trials also suggest that use of LABA as monotherapy increases the risk of asthma-related hospitalization in pediatric and adolescent patient
• 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

Dosing frequency should not exceed q12hr

Aerosol not recommended when patient is being switched from PO to inhaled corticosteroids

Risk of localized Candida albicans infections in mouth and pharynx in some patients; when such an infection develops, it should be treated with appropriate local or systemic (ie, oral) antifungal therapy while treatment continues, but at times therapy may need to be interrupted; mouth must be rinsed after dosing to reduce risk

Monitor COPD patients for signs and symptoms of pneumonia and lung infection

Risk of more serious or fatal course of chickenpox or measles in susceptible patients (eg, unvaccinated or immunologically unexposed individuals); care must be taken to avoid exposure

Particular care is needed in switching patients from systemic to inhaled corticosteroids; potentially fatal adrenal insufficiency may occur before or afterward; taper withdrawal gradually by reducing daily prednisone dose by 2.5 mg on weekly basis

During stress or severe asthma attack, patients who have been withdrawn from systemic corticosteroids should resume PO corticosteroids immediately

Risk of paradoxical bronchospasm, which may be life-threatening; discontinue, and treat immediately with inhaled SABA

Cardiovascular and central nervous system (CNS) effects may occur as consequences of excess beta-adrenergic stimulation; may result in asthma-related death; caution is advised in patients with cardiovascular or convulsive disorders or thyrotoxicosis

Bone mineral density may decrease after long-term administration of corticosteroids; monitor patients at risk

Should not be used for relief of acute symptoms, like, rescue therapy for treatment of acute episodes of bronchospasm; acute symptoms should be treated with inhaled, short-acting beta2-agonist

May decrease growth velocity in children; monitor

Risk of cataracts, glaucoma, and increased intraocular pressure

Rare cases of vasculitis (Churg-Strauss syndrome) or other systemic eosinophilic conditions may occur

Use caution in patients with diabetes mellitus; beta2 agonists may increase glucose levels

Use caution in patients with hepatic impairment; may lead to accumulation of fluticasone in plasma; monitor closely; glaucoma: consider eye exams in chronic users

Use caution in patients with seizure disorders; beta-agonists may result in CNS stimulation/excitation

Changes in thyroid status may require dosage adjustments; hyperthyroidism may increase corticosteroids clearance while it may decrease in hypothyroidism

Prolonged corticosteroid use may increase incidence of secondary infection, mask acute infection, prolong or exacerbate viral infections, or limit response to vaccines

Corticosteroids may cause psychiatric manifestations, including depression, euphoria, insomnia, mood swings, and personality changes; may also exacerbate preexisting psychiatric conditions

Laryngeal spasm, irritation and swelling (choking) may occur

Risk of transient hypokalemia; supplementation may not be required

Long-acting beta-agonist (LABA) monotherapy increases risk of serious asthma-related events

Not for use in acutely deteriorating asthma or COPD; not for treatment of acute symptoms

Potential worsening of infections (eg, existing tuberculosis; fungal, bacterial, viral, or parasitic infections; ocular herpes simplex); use caution in patients with these infections

Should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines containing LABA (eg, salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) as an overdose may result; clinically significant cardiovascular effects and fatalities reported in association with excessive use of inhaled sympathomimetic drugs; patients receiving therapy should not use another medicine containing a LABA for any reason

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 risk of developing a disseminated infection is not known
• The contribution of the underlying disease and/or prior corticosteroid treatment to 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

Transferring patients from systemic corticosteroid therapy

• Particular care 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 treatment 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 aerosol formulation or inhaler, Lung function (mean forced expiratory volume in 1 second [FEV1] 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 resulting from systemic corticosteroid suppression

  • Transfer of patients from systemic corticosteroid therapy may unmask allergic conditions previously suppressed by systemic corticosteroid therapy (eg, rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions)

• Corticosteroid withdrawal symptoms

  • During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal (eg, joint and/or muscular pain, lassitude, depression) despite maintenance or even improvement of respiratory function

Hypercorticism and adrenal suppression

• Fluticasone propionate, a component of the aerosol and inhaler formulations, 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 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 the drug combinaton
• Because of possibility of significant systemic absorption of inhaled corticosteroids, patients treated with the combination drug 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, the dose should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids, and for management of asthma symptoms

Pregnancy

There are no randomized clinical studies in pregnant women; in women with poorly or moderately controlled asthma, there is increased risk of several perinatal adverse outcomes such as pre-eclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate; pregnant women with asthma should be closely monitored and medication adjusted as necessary to maintain optimal asthma control of asthma

Labor and delivery

• There are no human studies evaluating effects of therapy during labor and delivery; because of potential for beta-agonist interference with uterine contractility, use of drug during labor should be restricted to those patients in whom benefits clearly outweigh the risks

Lactation

There are no available data on presence of fluticasone propionate or salmeterol in human milk, effects on breastfed child, or effects on milk production; other corticosteroids have been detected in human milk; however, fluticasone propionate and salmeterol concentrations in plasma after inhaled therapeutic doses are low and therefore concentrations in human breast milk are likely to be correspondingly low; developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy and any potential adverse effects on breastfed child from therapy or from underlying maternal condition

Measurable levels of salmeterol and fluticasone detected in lactating rats treated with each drug

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Salmeterol: Selective LABA; stimulates intracellular adenyl cyclase resulting in increased cAMP levels causing bronchial smooth muscle relaxation; also inhibits release of mediators of immediate hypersensitivity from cells, especially from mast cells

Fluticasone: Trifluorinated corticosteroid with potent anti-inflammatory activity; inhibits multiple cell types (eg, mast cells, eosinophils, basophils, lymphocytes, macrophages, neutrophils) and mediator production or secretion (eg, histamine, eicosanoids, leukotrienes, cytokines) involved in the asthmatic response

Absorption

Bioavailability: Fluticasone, 5%

Onset (salmeterol): Asthma, 30-48 min; COPD, 2 hr

Onset (fluticasone): >1-2 weeks

Peak plasma time: Fluticasone, 1-2 hr; salmeterol, 20 min

Peak plasma concentration: Fluticasone, 110 pg/mL; salmeterol, 196-223 pg/mL

Time to peak effect (salmeterol): Asthma, 3 hr; COPD, 2-5 hr

Distribution

Protein bound: Fluticasone, 99%; salmeterol, 96%

Vd: Fluticasone, 4.2 L/kg

Metabolism

Minimally metabolized, because of minimal absorption

Fluticasone metabolized in liver by CYP3A4 to metabolite with negligible activity; salmeterol extensively metabolized by hydroxylation

Elimination

Half-life: Fluticasone, 11-12 hr; salmeterol, 5.5 hr

Excretion (fluticasone): Feces (95%), urine (5%)

Excretion (salmeterol): Feces (60%), urine (25%)

Diskus Oral Inhalation Preparation

Remove from foil pouch before first time use; indicate date opened on diskus

Open top cover; slide lever until it clicks

Avoid closing or tilting the diskus

Diskus Oral Inhalation Administration

For oral inhalation only

Breathe out fully through your mouth, expelling as much air from lungs as possible; hold diskus upright, placing the mouthpiece fully into the mouth, closing your lips around it

Continue breathing in slowly until lungs are full; avoid breathing out

Hold breath as comfortably possible, up to 10 sec

Remove diskus from mouth; breathe through nose while keeping lips closed;

Close cover after use; rinse mouth out with water (do not swallow water)

Inhaler Oral Inhalation Preparation

Priming aerosolized inhalers

• Prime inhaler before first use or unused for > 4 wks
• Release 3 test puffs into air, away from face
• Remove cap; shake well for 5 sec before each test puff

Instructions

• Check mouthpiece for objects before use
• Make sure canister is fully inserted
• Shake well before each use

Inhaler Oral Inhalation Administration

For oral inhalation only

Remove cap; place middle or index finger on canister top while placing thumb underneath mouthpiece

Breathe out fully through your mouth, expelling as much air from lungs as possible; hold inhaler upright, placing the mouthpiece fully into the mouth, closing your lips around it

While pushing firmly on canister top, continue breathing in slowly until lungs are full; avoid breathing out

Hold breath as comfortably possible, up to 10 sec

Remove inhaler from mouth; breathe through nose while keeping lips closed

Repeating dose

• Wait at least 30 seconds prior preceding second puff
• Shake well prior to use; repeat steps (See Inhaler Oral Inhalation Administration)
• Replace the cap after use
• When finished administering 2 puffs, rinse mouth out with water (do not swallow water)

Cleaning

Wash and dry mouthpiece at least weekly

When mouthpiece becomes blocked, wash mouthpiece thoroughly