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; mouth must be rinsed after inhalation 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

Excessive use may suppress hypothalamic-pituitary-adrenal function; monitor closely, especially postoperatively or during periods of stress

Hypercorticism and adrenal suppression may occur even at regular dosage in susceptible individuals; if such changes occur, discontinue therapy slowly

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

Not for use in combination with an additional medicine containing a LABA because of risk of overdose

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

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