salmeterol/fluticasone inhaled (Advair Diskus, Advair HFA)

Dosing and uses of Advair Diskus, Advair HFA (salmeterol/fluticasone inhaled)

• Adult
• Pediatric

 

Adult dosage forms and strengths

salmeterol/fluticasone inhaled

powder for inhalation

• (50mcg/100mcg)/actuation
• (50mcg/250mcg)/actuation
• (50mcg/500mcg)/actuation

aerosol for inhalation

• (21mcg/45mcg)/actuation
• (21mcg/115mcg)/actuation
• (21mcg/230mcg)/actuation

 

Asthma

Inhaled powder: 1 actuation PO q12hr (initial dose determined by asthma severity); not to exceed 1 actuation of 50 mcg/500 mcg q12hr

Inhaled aerosol: 2 actuations PO q12hr (initial dose determined by asthma severity); not to exceed 2 actuations of 21 mcg/230 mcg q12hr

 

Chronic Obstructive Pulmonary Disease

Inhaled powder: 1 actuation of 50 mcg/250 mcg PO q12hr

 

Exophthalmos (Orphan)

Treatment of symptomatic exophthalmos associated with thyroid-related eye disease

Orphan sponsor

• Lithera, Inc, 9191 Towne Center Drive, San Diego, CA 92122

 

Dosing Considerations

Inhaled powder: If dyspnea occurs between doses, chronic obstructive pulmonary disease (COPD) patients may take inhaled short-acting beta agonist (SABA) for immediate relief

 

Pediatric dosage forms and strengths

salmeterol/fluticasone inhaled

powder for inhalation

• (50mcg/100mcg)/actuation
• (50mcg/250mcg)/actuation
• (50mcg/500mcg)/actuation

aerosol for inhalation

• (21mcg/45mcg)/actuation
• (21mcg/115mcg)/actuation
• (21mcg/230mcg)/actuation

 

Asthma

Inhaled powder

• <4 years: Safety and efficacy not established
• 4-12 years: 1 actuation of 50 mcg/100 mcg PO q12hr
• ≥12 years: 1 actuation PO q12hr (initial dose determined by asthma severity); not to exceed 1 actuation of 50 mcg/500 mcg q12hr

Inhaled aerosoL

• <12 years: Safety and efficacy not established
• ≥12 years: 2 actuations PO q12hr (initial dose determined by asthma severity); not to exceed 2 actuations of 21 mcg/230 mcg q12hr

 

Advair Diskus, Advair HFA (salmeterol/fluticasone inhaled) adverse (side) effects

>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

Ophthalmologic: Glaucoma

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

 

Warnings

Black box warnings

Long-acting beta agonists (LABAs), such as salmeterol, may increase risk of asthma-related death; therefore, they should be used only as additional therapy for patients whose asthma is not adequately controlled on other asthma-control medications (eg, low- to medium-dose inhaled corticosteroids) or whose disease severity clearly warrants initiation of treatment with 2 maintenance therapies, including LABAs

Because of risk, use of LABAs without concomitant long-term asthma-control medication (eg, inhaled corticosteroid) is contraindicated

Once asthma control is achieved or maintained, assess at regular intervals; step down therapy (eg, discontinue LABA) if doing so is possible without loss of asthma control, and maintain patient on long-term asthma-control medication (eg, inhaled corticosteroid)

Do not use LABAs if asthma is adequately controlled on low- or medium-dose inhaled corticosteroids

Controlled clinical trials suggest that LABAs increase risk of asthma-related hospitalization in pediatric and adolescent patients; if such patients require addition of LABA to inhaled corticosteroid, use fixed-dose combination product containing both inhaled corticosteroid and LABA to ensure adherence

 

Contraindications

Hypersensitivity to drug, components of frmulation, or milk proteins, which may result in anaphylaxis, angioedema, rash, and urticaria

Not to be used as rescue therapy for status asthmaticus, acute bronchospasm

Patients with acute asthma, pulmonary tuberculosis, arrhythmias, or acute COPd

Aerosol not indicated in pediatric patients

 

Cautions

Dosing frequency should not exceed q12hr

Risk of potentially fatal acute asthma

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

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

May decrease growth velocity in children

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

 

Pregnancy and lactation

Pregnancy category: C

Lactation: Unknown whether agent is excreted in breast milk; salmeterol plasma levels are very low after inhalation

 

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.

 

Pharmacology of Advair Diskus, Advair HFA (salmeterol/fluticasone inhaled)

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%)